Small molecule inhibitors of the nuclear translocation of androgen receptor for the treatment of castration-resistant prostate cancer

ABSTRACT

A compound, or a pharmaceutically acceptable salt or ester thereof, according to formula I: 
       R 20 -(Z) b -(Y) c —(R 21 ) a —(X) d —R 22 —R 23  
 
     wherein R 20  is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; Z is alkanediyl, substituted alkanediyl, cycloalkanediyl, or substituted cycloalkanediyl; Y is S, O, S(═O), —S(═O)(═O)—, or NR 10 , wherein R 10  is H or alkyl; R 21  is alkanediyl, substituted alkanediyl, cycloalkanediyl, substituted cycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl, substituted cycloalkenediyl, alkatrienyl, substituted alkatrienyl; X is —C(═O)—, —S(═O)(═O)—, or —N(H)C(═O)—; R 22  includes at least one divalent amino radical; R 23  is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; a, b, c, and d independently are 0 or 1.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT Application No.PCT/US2017/024105, filed Mar. 24, 2017, which is a continuation-in-partof U.S. application Ser. No. 15/080,237, filed Mar. 24, 2016, nowabandoned, and this application further claims the benefit of theearlier filing date of U.S. Provisional Application No. 62/671,254,filed May 14, 2018, each of which is incorporated in its entirety hereinby reference.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant #GM067082awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND

Castration-resistant prostate cancer (CRPC) is currently incurable andmakes prostate cancer the second most common cause of cancer death amongmen in the United States. The androgen receptor (AR) is activated viamultiple mechanisms including AR overexpression, mutation,hypersensitization, and/or intratumoral androgen synthesis in patientsrelapsed after androgen deprivation therapy (ADT). The steroidalhormones testosterone and dihydrotestosterone are the major endogenousandrogens that cause nuclear translocation and subsequent activation ofandrogen receptor (AR). Overexpression and knockdown studies havedemonstrated that AR is a key molecular determinant and an excellenttherapeutic target for CRPC. Clinical use of abiraterone, a potentinhibitor of testosterone synthesis, and MDV3100 (enzalutamide) andbicalutamide, AR antagonists, indicates that AR remains a viable targetin a significant number of CRPC patients.

Androgen receptor (AR), a member of the steroid receptor superfamily, isa ligand-dependent transcription factor that controls the expression ofandrogen-responsive genes. Intracellular trafficking is an importantmechanism in the regulation of many transcription factors, including AR.In order to access its target genes, a transcription factor requireslocalization to the nucleus. Retention of a transcription factor in thecytoplasm prevents its activity. Thus, a key regulatory step in theaction of AR is its nuclear translocation. In androgen-sensitive cells,AR is localized to the cytoplasm in the absence of ligand. Upon additionof androgens, AR translocates to the nucleus and transactivates targetgenes. However, in CRPC cells, AR remains in the nucleus even in theabsence of androgen and transactivates androgen-responsive genes,leading to uncontrolled growth of prostate tumors. Therefore, novelapproaches that can block the nuclear localization of AR, degradenuclear AR, and/or suppress nuclear AR activity may provide an effectivetherapy against CRPC.

SUMMARY

Disclosed herein is a compound, or a pharmaceutically acceptable salt orester thereof, having a formula I of:

R²⁰-(Z)_(b)-(Y)_(c)—(R²¹)_(a)—(X)_(d)—R²²—R²³

wherein R²⁰ is an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,substituted heterocycloalkyl, alkoxy, aryloxy, amino, a thio-containinggroup, or a seleno-containing group; Z is alkanediyl, substitutedalkanediyl, cycloalkanediyl, or substituted cycloalkanediyl; Y is S, O,S(═O), —S(═O)(═O)—, or NR¹⁰, wherein R¹⁰ is H or alkyl; R²¹ isalkanediyl, substituted alkanediyl, cycloalkanediyl, substitutedcycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl,substituted cycloalkenediyl, alkatrienyl, substituted alkatrienyl; X is—C(═O)—, —S(═O)(═O)—, or —N(H)C(═O)—; R²² is a moiety that includes atleast one divalent amino radical; R²³ is an aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, amino,a thio-containing group, a seleno-containing group; a is 0 or 1; b is 0or 1; c is 0 or 1; and d is 0 or 1. In some embodiments, if X is —C(═O)—then Y is not S. In certain embodiments, R²¹ is cycloalkanediyl. WhenR²¹ is cycloalkanediyl, R²⁰ may be a phenyl optionally substituted withat least one halogen and/or R²³ may be a phenyl substituted with atleast one halogen and/or at least one alkyl.

Also disclosed herein is a method for treating prostate cancer in asubject, comprising administering a therapeutically effective amount ofan agent to the subject, wherein the agent is a compound, or apharmaceutically acceptable salt or ester thereof, of formula I orformula II.

The foregoing will become more apparent from the following detaileddescription, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A through 1D are a table showing compound structures.

FIGS. 2A through 2J show additional compound structures.

FIGS. 3A through 3E show assay results for several of the compounds.C4-2 cells were transfected with PSA6.1-Luc, GFP-AR, and pRL-CMV andthen treated with indicated doses for 24 hours. For luciferase assays,cells were lysed with passive lysis buffer (Promega) and both Fireflyand Renilla luciferase activities were read using a Dual-LuciferaseReporter Assay kit (Promega) on a LmaxII384 luminometer (MolecularDevices). Firefly luciferase values were normalized to Renilla(pRL-CMV). Plotted values represent averaged normalized Fireflyluciferase activities, each performed in triplicate, relative to DMSOcontrol. This assay is described in more detail in PCT PatentApplication Publication WO 2013055793, which is incorporated herein byreference.

FIG. 4 is a reaction scheme showing the synthesis of2-((isoxazol-4-ylmethyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone 1.

FIG. 5 is a chemical structure of2-((isoxazol-4-ylmethyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone showingzones of modification.

FIG. 6 is a reaction scheme showing synthesis of certain embodiments ofthe disclosed compounds. Reagents and conditions: (a) T3P(propylphosphonic anhydride), Et₃N (triethylamine), CH₂Cl₂, rt (roomtemperature), overnight, 52-98%; (b) LiAlH₄, dry THF (tetrahydrofuran),0° C., 1 h, 42%; (c) NaIO₄, MeOH (methanol), H₂O, rt, 15 h, 68%; (d)m-CPBA (meta-chloroperoxybenzoic acid), CH₂Cl₂, rt, 15 h, 44%.

FIG. 7 is a reaction scheme showing synthesis of certain embodiments ofthe disclosed compounds. Reagents and conditions: (a) T3P, Et₃N, CH₂Cl₂,rt, overnight, 62-96%; (b) Lindlar's catalyst, quinoline, H₂, EtOAc(ethyl acetate), quant.; (c) CrCl₂, CH₂ICl, THF, reflux, overnight, 57%.

FIG. 8 is a reaction scheme showing synthesis of certain embodiments ofthe disclosed compounds. Reagents and conditions: (a) 2-chloroacetylchloride, Et₃N, CH₂Cl₂, rt, overnight, 99%; (b) chloromethanesulfonylchloride, Et₃N, CH₂Cl₂, rt, overnight, 85%; (c) NaH, THF, rt, 1-2 d,4-99%; (d) DPPA (diphenyl phosphoryl azide), Et₃N, toluene, reflux,overnight, 17-65%.

FIG. 9 is a reaction scheme showing synthesis of certain embodiments ofthe disclosed compounds. Reagents and conditions: (a) Boc₂O, DMAP,CH₂Cl₂, rt, overnight, 78%; (b) NaHMDS (sodiumbis(trimethylsilyl)amide), PhNTf₂(N-phenyl-bis(tifluoromethanesulfonamide), THF, −78° C. to rt, 4 h, 78%;(c) Pd(PPh₃)₄, LiCl, Na₂CO₃, (2-Me)PhB(OH)₂, DME (dimethoxyethane), H₂O,60° C., 3 h, 78%; (d) H₂, Pd/C, EtOH (ethanol), rt, 14 h, 90%; (e) TFA(trifluoroacetic acid), CH₂Cl₂, rt, 16 h, quant.; (f) 2-chloroacetylchloride, Et₃N, THF, rt, 22 h, 79%; (g) 25, NaH, THF, rt, 1 d, 30%.

FIG. 10A is a graph showing the effect of compound #583 at indicatedconcentrations on PSA-driven luciferase activity in C4-2 cells.

FIG. 10B shows the effect of compound #583 at indicated concentrationson C4-2 cell proliferation in BrdU assay.

FIG. 10C shows the effect of analog #583 at indicated concentrations onPC3 cell proliferation in BrdU assay.

FIG. 11 is a graph showing the effect of compound #571 at indicatedconcentrations on PSA-driven luciferase activity in C4-2 cells.

FIG. 12 is a graph showing the effect of compound JJ-450 at indicatedconcentrations on 22Rv1 xenograft tumor volume. JJ-450 was injected i.p.daily.

FIG. 13 is a graph showing the effect of compound JJ-450 at indicatedconcentrations and administration route on LNCaP xenograft tumor volume.JJ-450 was administered 6 times, from Monday to Saturday, every week

FIGS. 14-35 are reaction schemes showing synthesis of certainembodiments of the disclosed compounds.

DETAILED DESCRIPTION

The following explanations of terms and methods are provided to betterdescribe the present compounds, compositions and methods, and to guidethose of ordinary skill in the art in the practice of the presentdisclosure. It is also to be understood that the terminology used in thedisclosure is for the purpose of describing particular embodiments andexamples only and is not intended to be limiting.

“Administration of” and “administering a” compound should be understoodto mean providing a compound, a prodrug of a compound, or apharmaceutical composition as described herein. The compound orcomposition can be administered by another person to the subject (e.g.,intravenously) or it can be self-administered by the subject (e.g.,tablets).

“Alkanediyl” or “cycloalkanediyl” refers to a divalent radical of thegeneral formula —C_(n)H_(2n)— or —C_(n)H_(2n-2)—, respectively, derivedfrom aliphatic or cycloaliphatic hydrocarbons. “Cycloalkenediyl” refersto a divalent radical of the general formula —C_(n)H_(2n-4)— derivedfrom a cycloalkene.

The term “aliphatic” is defined as including alkyl, alkenyl, alkynyl,halogenated alkyl and cycloalkyl groups as described above. A “loweraliphatic” group is a branched or unbranched aliphatic group having from1 to 10 carbon atoms.

The term “alkyl” refers to a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl,octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A“lower alkyl” group is a saturated branched or unbranched hydrocarbonhaving from 1 to 6 carbon atoms. Preferred alkyl groups have 1 to 4carbon atoms. Alkyl groups may be “substituted alkyls” wherein one ormore hydrogen atoms are substituted with a substituent such as halogen,cycloalkyl, alkoxy, amino, hydroxyl, aryl, alkenyl, or carboxyl. Forexample, a lower alkyl or (C₁-C₆)alkyl can be methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl;(C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl;(C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl; halo(C₁-C₆)alkylcan be iodomethyl, bromomethyl, chloromethyl, fluoromethyl,trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, orpentafluoroethyl; hydroxy(C₁-C₆)alkyl can be hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl,3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl,5-hydroxypentyl, 1-hydroxyhexyl, or 6-hydroxyhexyl;(C₁-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; (C₁-C₆)alkylthio can be methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, orhexylthio; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,isobutanoyloxy, pentanoyloxy, or hexanoyloxy.

The term “alkylaryl” refers to a group in which an alkyl group issubstituted for a hydrogen atom of an aryl group. An example is —Ar—R,wherein Ar is an arylene group and R is an alkyl group.

The term “alkoxy” refers to a straight, branched or cyclic hydrocarbonconfiguration and combinations thereof, including from 1 to 20 carbonatoms, preferably from 1 to 8 carbon atoms (referred to as a “loweralkoxy”), more preferably from 1 to 4 carbon atoms, that include anoxygen atom at the point of attachment. An example of an “alkoxy group”is represented by the formula —OR, where R can be an alkyl group,optionally substituted with an alkenyl, alkynyl, aryl, aralkyl,cycloalkyl, halogenated alkyl, alkoxy or heterocycloalkyl group.Suitable alkoxy groups include methoxy, ethoxy, n-propoxy, propoxy,n-butoxy, i-butoxy, sec-butoxy, tert-butoxy cyclopropoxy, cyclohexyloxy,and the like.

“Alkoxycarbonyl” refers to an alkoxy substituted carbonyl radical,—C(O)OR, wherein R represents an optionally substituted alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.

“Alkynyl” refers to a cyclic, branched or straight chain groupcontaining only carbon and hydrogen, and unless otherwise mentionedtypically contains one to twelve carbon atoms, and contains one or moretriple bonds. Alkynyl groups may be unsubstituted or substituted. “Loweralkynyl” groups are those that contain one to six carbon atoms.

The term “amide” or “amido” is represented by the formula —C(O)NRR′,where R and R′ independently can be a hydrogen, alkyl, alkenyl, alkynyl,aryl, arylalkyl, cycloalkyl, halogenated alkyl, or heterocycloalkylgroup described above. A suitable amido group is acetamido.

The term “amine” or “amino” refers to a group of the formula NRR′, whereR and R′ can be, independently, hydrogen or an alkyl, alkenyl, alkynyl,aryl, arylalkyl, carbonyl (e.g, —C(O)R″, where R″ can be hydrogen, analkyl, alkenyl, alkynyl, aryl, or an arylalkyl), cycloalkyl, halogenatedalkyl, or heterocycloalkyl group. For example, an “alkylamino” or“alkylated amino” refers to —NRR′, wherein at least one of R or R′ is analkyl.

“Aminocarbonyl” alone or in combination, means an amino substitutedcarbonyl (carbamoyl) radical, wherein the amino radical may optionallybe mono- or di-substituted, such as with alkyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyland the like. An aminocarbonyl group may be —C(O)—N(R) (wherein R is asubstituted group or H). An “aminocarbonyl” is inclusive of an amidogroup. A suitable aminocarbonyl group is acetamido.

An “analog” is a molecule that differs in chemical structure from aparent compound, for example a homolog (differing by an increment in thechemical structure or mass, such as a difference in the length of analkyl chain or the inclusion of one of more isotopes), a molecularfragment, a structure that differs by one or more functional groups, ora change in ionization. An analog is not necessarily synthesized fromthe parent compound. Structural analogs are often found usingquantitative structure activity relationships (QSAR), with techniquessuch as those disclosed in Remington (The Science and Practice ofPharmacology, 19th Edition (1995), chapter 28). A derivative is amolecule derived from the base structure.

An “animal” refers to living multi-cellular vertebrate organisms, acategory that includes, for example, mammals and birds. The term mammalincludes both human and non-human mammals. Similarly, the term “subject”includes both human and non-human subjects, including birds andnon-human mammals, such as non-human primates, companion animals (suchas dogs and cats), livestock (such as pigs, sheep, cows), as well asnon-domesticated animals, such as the big cats. The term subject appliesregardless of the stage in the organism's life-cycle. Thus, the termsubject applies to an organism in utero or in ovo, depending on theorganism (that is, whether the organism is a mammal or a bird, such as adomesticated or wild fowl).

The term “aryl” refers to any carbon-based aromatic group including, butnot limited to, phenyl, naphthyl, etc. The term “aryl” also includes“heteroaryl group,” which is defined as an aromatic group that has atleast one heteroatom incorporated within the ring of the aromatic group.Examples of heteroatoms include, but are not limited to, nitrogen,oxygen, sulfur, and phosphorous. The aryl group can be substituted withone or more groups including, but not limited to, alkyl, alkynyl,alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy,carboxylic acid, or alkoxy, or the aryl group can be unsubstituted.

The term “arylalkyl” refers to an alkyl group where at least onehydrogen atom is substituted by an aryl group. An example of anarylalkyl group is a benzyl group.

“Carbonyl” refers to a group of the formula —C(O)—. Carbonyl-containinggroups include any substituent containing a carbon-oxygen double bond(C═O), including acyl groups, amides, carboxy groups, esters, ureas,carbamates, carbonates and ketones and aldehydes, such as substituentsbased on —COR or —RCHO where R is an aliphatic, heteroaliphatic, alkyl,heteroalkyl, hydroxyl, or a secondary, tertiary, or quaternary amine.

“Carboxyl” refers to a —COO group. Substituted carboxyl refers to —COORwhere R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or acarboxylic acid or ester.

The term “cycloalkyl” refers to a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. The term “heterocycloalkyl group” is acycloalkyl group as defined above where at least one of the carbon atomsof the ring is substituted with a heteroatom such as, but not limitedto, nitrogen, oxygen, sulfur, or phosphorous.

The term “co-administration” or “co-administering” refers toadministration of a first agent with a second agent within the samegeneral time period, and does not require administration at the sameexact moment in time (although co-administration is inclusive ofadministering at the same exact moment in time). Thus, co-administrationmay be on the same day or on different days, or in the same week or indifferent weeks. The first agent and the second agent may be included inthe same composition or they may each individually be included inseparate compositions. In certain embodiments, the two agents may beadministered during a time frame wherein their respective periods ofbiological activity overlap. Thus, the term includes sequential as wellas coextensive administration of two or more agents.

“Derivative” refers to a compound or portion of a compound that isderived from or is theoretically derivable from a parent compound.

The terms “halogenated alkyl” or “haloalkyl group” refer to an alkylgroup as defined above with one or more hydrogen atoms present on thesegroups substituted with a halogen (F, Cl, Br, I).

The term “hydroxyl” is represented by the formula —OH.

The term “hydroxyalkyl” refers to an alkyl group that has at least onehydrogen atom substituted with a hydroxyl group. The term “alkoxyalkylgroup” is defined as an alkyl group that has at least one hydrogen atomsubstituted with an alkoxy group described above.

“Inhibiting” refers to inhibiting the full development of a disease orcondition. “Inhibiting” also refers to any quantitative or qualitativereduction in biological activity or binding, relative to a control.

“N-heterocyclic” refers to mono or bicyclic rings or ring systems thatinclude at least one nitrogen heteroatom. The rings or ring systemsgenerally include 1 to 9 carbon atoms in addition to the heteroatom(s)and may be saturated, unsaturated or aromatic (includingpseudoaromatic). The term “pseudoaromatic” refers to a ring system whichis not strictly aromatic, but which is stabilized by means ofdelocalization of electrons and behaves in a similar manner to aromaticrings. Aromatic includes pseudoaromatic ring systems, such as pyrrolylrings.

Examples of 5-membered monocyclic N-heterocycles include pyrrolyl,H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including1,2,3 and 1,2,4 oxadiazolyls) isoxazolyl, furazanyl, thiazolyl,isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl,imidazolinyl, triazolyl (including 1,2,3 and 1,3,4 triazolyls),tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls), anddithiazolyl. Examples of 6-membered monocyclic N-heterocycles includepyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, and triazinyl. The heterocycles may beoptionally substituted with a broad range of substituents, andpreferably with C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono ordi(C₁₋₆alkyl)amino. The N-heterocyclic group may be fused to acarbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl,and anthracenyl.

Examples of 8, 9 and 10-membered bicyclic heterocycles include 1Hthieno[2,3-c]pyrazolyl, indolyl, isoindolyl, benzoxazolyl,benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl,indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, purinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, and the like.These heterocycles may be optionally substituted, for example with C₁₋₆alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, hydroxy, mercapto,trifluoromethyl, amino, cyano or mono or di(C₁₋₆alkyl)amino. Unlessotherwise defined optionally substituted N-heterocyclics includespyridinium salts and the N-oxide form of suitable ring nitrogens.

Examples of N-heterocycles also include bridged groups such as, forexample, azabicyclo (for example, azabicyclooctane).

“Stereoisomers” are isomers that have the same molecular formula andsequence of bonded atoms, but which differ only in the three-dimensionalorientation of the atoms in space. By convention, bold wedge bonds areused to indicate bonds coming out of the page toward the reader, andhashed wedge bonds are used to indicate bonds going behind the page awayfrom the reader. Pairs of bold and hashed bonds that are not wedged areused to indicate bonds of the same orientation, i.e., a pair of bondsthat are both coming out of the page or going behind the page.

“Pharmaceutical compositions” are compositions that include an amount(for example, a unit dosage) of one or more of the disclosed compoundstogether with one or more non-toxic pharmaceutically acceptableadditives, including carriers, diluents, and/or adjuvants, andoptionally other biologically active ingredients. Such pharmaceuticalcompositions can be prepared by standard pharmaceutical formulationtechniques such as those disclosed in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. (19th Edition).

The terms “pharmaceutically acceptable salt or ester” refers to salts oresters prepared by conventional means that include salts, e.g., ofinorganic and organic acids, including but not limited to hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonicacid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid,tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid,maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelicacid and the like. “Pharmaceutically acceptable salts” of the presentlydisclosed compounds also include those formed from cations such assodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and frombases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane, andtetramethylammonium hydroxide. These salts may be prepared by standardprocedures, for example by reacting the free acid with a suitableorganic or inorganic base. Any chemical compound recited in thisspecification may alternatively be administered as a pharmaceuticallyacceptable salt thereof. “Pharmaceutically acceptable salts” are alsoinclusive of the free acid, base, and zwitterionic forms. Descriptionsof suitable pharmaceutically acceptable salts can be found in Handbookof Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH(2002). When compounds disclosed herein include an acidic function suchas a carboxy group, then suitable pharmaceutically acceptable cationpairs for the carboxy group are well known to those skilled in the artand include alkaline, alkaline earth, ammonium, quaternary ammoniumcations and the like. Such salts are known to those of skill in the art.For additional examples of “pharmacologically acceptable salts,” seeBerge et al., J. Pharm. Sci. 66:1 (1977).

“Pharmaceutically acceptable esters” includes those derived fromcompounds described herein that are modified to include a carboxylgroup. An in vivo hydrolysable ester is an ester which is hydrolysed inthe human or animal body to produce the parent acid or alcohol.Representative esters thus include carboxylic acid esters in which thenon-carbonyl moiety of the carboxylic acid portion of the ester groupingis selected from straight or branched chain alkyl (for example, methyl,n-propyl, t-butyl, or n-butyl), cycloalkyl, alkoxyalkyl (for example,methoxymethyl), arylalkyl (for example benzyl), aryloxyalkyl (forexample, phenoxymethyl), aryl (for example, phenyl, optionallysubstituted by, for example, halogen, C.sub.1-4 alkyl, or C.sub.1-4alkoxy) or amino); sulphonate esters, such as alkyl- orarylalkylsulphonyl (for example, methanesulphonyl); or amino acid esters(for example, L-valyl or L-isoleucyl). A “pharmaceutically acceptableester” also includes inorganic esters such as mono-, di-, ortri-phosphate esters. In such esters, unless otherwise specified, anyalkyl moiety present advantageously contains from 1 to 18 carbon atoms,particularly from 1 to 6 carbon atoms, more particularly from 1 to 4carbon atoms. Any cycloalkyl moiety present in such estersadvantageously contains from 3 to 6 carbon atoms. Any aryl moietypresent in such esters advantageously comprises a phenyl group,optionally substituted as shown in the definition of carbocycylyl above.Pharmaceutically acceptable esters thus include C₁-C₂₂ fatty acidesters, such as acetyl, t-butyl or long chain straight or branchedunsaturated or omega-6 monounsaturated fatty acids such as palmoyl,stearoyl and the like. Alternative aryl or heteroaryl esters includebenzoyl, pyridylmethyloyl and the like any of which may be substituted,as defined in carbocyclyl above. Additional pharmaceutically acceptableesters include aliphatic L-amino acid esters such as leucyl, isoleucyland especially valyl.

For therapeutic use, salts of the compounds are those wherein thecounter-ion is pharmaceutically acceptable. However, salts of acids andbases which are non-pharmaceutically acceptable may also find use, forexample, in the preparation or purification of a pharmaceuticallyacceptable compound.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds are ableto form. The pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds containing an acidic proton may also be converted intotheir non-toxic metal or amine addition salt forms by treatment withappropriate organic and inorganic bases. Appropriate base salt formscomprise, for example, the ammonium salts, the alkali and earth alkalinemetal salts, e.g. the lithium, sodium, potassium, magnesium, calciumsalts and the like, salts with organic bases, e.g. the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like.

The term “addition salt” as used hereinabove also comprises the solvateswhich the compounds described herein are able to form. Such solvates arefor example hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds are able to form by reaction betweena basic nitrogen of a compound and an appropriate quaternizing agent,such as, for example, an optionally substituted alkylhalide, arylhalideor arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactantswith good leaving groups may also be used, such as alkyltrifluoromethanesulfonates, alkyl methanesulfonates, and alkylp-toluenesulfonates. A quaternary amine has a positively chargednitrogen. Pharmaceutically acceptable counterions include chloro, bromo,iodo, trifluoroacetate and acetate. The counterion of choice can beintroduced using ion exchange resins.

It will be appreciated that the compounds described herein may havemetal binding, chelating, complex forming properties and therefore mayexist as metal complexes or metal chelates.

Some of the compounds described herein may also exist in theirtautomeric form.

The term “subject” includes both human and veterinary subjects.

A “therapeutically effective amount” or “diagnostically effectiveamount” refers to a quantity of a specified agent sufficient to achievea desired effect in a subject being treated with that agent. Ideally, atherapeutically effective amount or diagnostically effective amount ofan agent is an amount sufficient to inhibit or treat the disease withoutcausing a substantial cytotoxic effect in the subject. Thetherapeutically effective amount or diagnostically effective amount ofan agent will be dependent on the subject being treated, the severity ofthe affliction, and the manner of administration of the therapeuticcomposition.

“Treatment” refers to a therapeutic intervention that ameliorates a signor symptom of a disease or pathological condition after it has begun todevelop. As used herein, the term “ameliorating,” with reference to adisease or pathological condition, refers to any observable beneficialeffect of the treatment. The beneficial effect can be evidenced, forexample, by a delayed onset of clinical symptoms of the disease in asusceptible subject, a reduction in severity of some or all clinicalsymptoms of the disease, a slower progression of the disease, animprovement in the overall health or well-being of the subject, or byother parameters well known in the art that are specific to theparticular disease. The phrase “treating a disease” is inclusive ofinhibiting the full development of a disease or condition, for example,in a subject who is at risk for a disease, or who has a disease, such ascancer or a disease associated with a compromised immune system.“Preventing” a disease or condition refers to prophylactic administeringa composition to a subject who does not exhibit signs of a disease orexhibits only early signs for the purpose of decreasing the risk ofdeveloping a pathology or condition, or diminishing the severity of apathology or condition.

Prodrugs of the disclosed compounds also are contemplated herein. Aprodrug is an active or inactive compound that is modified chemicallythrough in vivo physiological action, such as hydrolysis, metabolism andthe like, into an active compound following administration of theprodrug to a subject. The term “prodrug” as used throughout this textmeans the pharmacologically acceptable derivatives such as esters,amides and phosphates, such that the resulting in vivo biotransformationproduct of the derivative is the active drug as defined in the compoundsdescribed herein. Prodrugs preferably have excellent aqueous solubility,increased bioavailability and are readily metabolized into the activeinhibitors in vivo. Prodrugs of a compounds described herein may beprepared by modifying functional groups present in the compound in sucha way that the modifications are cleaved, either by routine manipulationor in vivo, to the parent compound. The suitability and techniquesinvolved in making and using prodrugs are well known by those skilled inthe art. For a general discussion of prodrugs involving esters seeSvensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard,Design of Prodrugs, Elsevier (1985).

The term “prodrug” also is intended to include any covalently bondedcarriers that release an active parent drug of the present invention invivo when the prodrug is administered to a subject. Since prodrugs oftenhave enhanced properties relative to the active agent pharmaceutical,such as, solubility and bioavailability, the compounds disclosed hereincan be delivered in prodrug form. Thus, also contemplated are prodrugsof the presently disclosed compounds, methods of delivering prodrugs andcompositions containing such prodrugs. Prodrugs of the disclosedcompounds typically are prepared by modifying one or more functionalgroups present in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to yield the parentcompound. Prodrugs include compounds having a phosphonate and/or aminogroup functionalized with any group that is cleaved in vivo to yield thecorresponding amino and/or phosphonate group, respectively. Examples ofprodrugs include, without limitation, compounds having an acylated aminogroup and/or a phosphonate ester or phosphonate amide group. Inparticular examples, a prodrug is a lower alkyl phosphonate ester, suchas an isopropyl phosphonate ester.

Protected derivatives of the disclosed compounds also are contemplated.A variety of suitable protecting groups for use with the disclosedcompounds are disclosed in Greene and Wuts, Protective Groups in OrganicSynthesis; 3rd Ed.; John Wiley & Sons, New York, 1999.

In general, protecting groups are removed under conditions which willnot affect the remaining portion of the molecule. These methods are wellknown in the art and include acid hydrolysis, hydrogenolysis and thelike. One preferred method involves the removal of an ester, such ascleavage of a phosphonate ester using Lewis acidic conditions, such asin TMS-Br mediated ester cleavage to yield the free phosphonate. Asecond preferred method involves removal of a protecting group, such asremoval of a benzyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxy-based group, including t-butoxycarbonyl protecting groups can be removed utilizing an inorganic ororganic acid, such as HCl or trifluoroacetic acid, in a suitable solventsystem, such as water, dioxane and/or methylene chloride. Anotherexemplary protecting group, suitable for protecting amino and hydroxyfunctions amino is trityl. Other conventional protecting groups areknown and suitable protecting groups can be selected by those of skillin the art in consultation with Greene and Wuts, Protective Groups inOrganic Synthesis; 3rd Ed.; John Wiley & Sons, New York, 1999. When anamine is deprotected, the resulting salt can readily be neutralized toyield the free amine Similarly, when an acid moiety, such as aphosphonic acid moiety is unveiled, the compound may be isolated as theacid compound or as a salt thereof.

Particular examples of the presently disclosed compounds include one ormore asymmetric centers; thus these compounds can exist in differentstereoisomeric forms. Accordingly, compounds and compositions may beprovided as individual pure enantiomers or as stereoisomeric mixtures,including racemic mixtures. In certain embodiments the compoundsdisclosed herein are synthesized in or are purified to be insubstantially enantiopure form, such as in a 90% enantiomeric excess, a95% enantiomeric excess, a 97% enantiomeric excess or even in greaterthan a 99% enantiomeric excess, such as in enantiopure form.

Groups which are substituted (e.g. substituted alkyl), may in someembodiments be substituted with a group which is substituted (e.g.substituted aryl). In some embodiments, the number of substituted groupslinked together is limited to two (e.g. substituted alkyl is substitutedwith substituted aryl, wherein the substituent present on the aryl isnot further substituted). In some embodiments, a substituted group isnot substituted with another substituted group (e.g. substituted alkylis substituted with unsubstituted aryl).

Overview

CRPC is responsible for all prostate cancer deaths, and eventually allprostate cancer will develop into CRPC. The current best treatment forCRPC is MDV3100 (enzalutamide), which binds to androgen receptor. It iseffective against a number of androgen-dependent prostate cancer celllines. However, it is ineffective against the androgen-dependentprostate cancer cell line 22Rv1. Compounds disclosed herein areeffective against all androgen-dependent cell lines tested including22Rv1, a promising and unique property.

Several of the compounds show sub-micromolar inhibition ofPSA-luciferase expression in C4-2 cells. Further, cell proliferation inandrogen-dependent cell lines is significantly decreased whileproliferation in androgen-independent cell lines is unaffected.

Agents

Disclosed herein are agents that can be used for treating prostatecancer, particularly castration-resistant prostate cancer. The agentsmay inhibit AR nuclear localization and/or reduce AR levels incastration-resistant prostate cancer.

In one embodiment, the agent is a compound, or a pharmaceuticallyacceptable salt or ester thereof, having a formula I of:

R²⁰-(Z)_(b)-(Y)_(c)—(R²¹)_(a)—(X)_(d)—R²²—R²³

wherein R²⁰ is an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group,a seleno-containing group, halide, or a nitro-containing group;

Z is alkanediyl, substituted alkanediyl, cycloalkanediyl, or substitutedcycloalkanediyl;

Y is S, O, S(═O), —S(═O)(═O)—, or NR¹⁰, wherein R¹⁰ is H or alkyl(preferably methyl);

R²¹ is alkanediyl, substituted alkanediyl, cycloalkanediyl, substitutedcycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl,substituted cycloalkenediyl, alkatrienyl, or substituted alkatrienyl;

X is —C(═O)—, —S(═O)(═O)—, or —N(H)C(═O)—;

R²² is a moiety that includes at least one divalent amino radical;

R²³ is an aryl, substituted aryl, heteroaryl, substituted heteroaryl,cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substitutedheterocycloalkyl, alkoxy, aryloxy, amino, a thio-containing group, or aseleno-containing group;

a is 0 or 1;

b is 0 or 1;

c is 0 or 1; and

d is 0 or 1.

In some embodiments, if X is —C(═O)— then Y is not S. In certainembodiments, R²¹ is cycloalkanediyl, such as cyclopropanediyl. When R²¹is cycloalkanediyl, R²⁰ may be a phenyl optionally substituted with atleast one halogen and/or R²³ may be a phenyl substituted with at leastone halogen and or at least one alkyl.

In certain embodiments, R²⁰ is selected from isoxazolyl, substitutedisoxazolyl (e.g, dialkyl-substituted such as dimethyl,hydroxy-substituted, hydroxyalkyl-substituted, or a combinationthereof), oxazolyl, substituted oxazolyl (e.g, dialkyl-substituted suchas dimethyl, hydroxy-substituted, hydroxyalkyl-substituted, or acombination thereof) cyclohexyl, substituted cyclohexyl (e.g.,hydroxy-substituted cyclohexyl), piperidinyl, substituted piperidinyl(e.g., hydroxy-substituted piperidinyl), oxacyclopentyl, substitutedoxacyclopentyl (e.g., hydroxyalkyl-substituted), oxacyclohexanyl,substituted oxacyclopentyl (e.g., hydroxyalkyl-substituted), thiophenyl,substituted thiophenyl (e.g., hydroxyalkyl-substituted), phenyl,substituted phenyl (e.g., hydroxyalkyl-substituted orhalogen-substituted), pyridinyl, substituted pyridinyl (e.g.,hydroxyalkyl-substituted), indolyl, substituted indolyl (e.g.,hydroxyalkyl-substituted), furanyl, substituted furanyl (e.g.,hydroxyalkyl-substituted), imidazolyl, substituted imidazolyl (e.g.,hydroxyalkyl-substituted). In preferred embodiments, R²⁰ is substitutedisoxazolyl, particularly dialkyl (e.g., dimethyl)-substitutedisooxazolyl, phenyl, or substituted phenyl, particularlyhalogen-substituted phenyl (e.g., fluorophenyl).

In certain embodiments, R²¹ is selected from C₁-C₃ alkanediyl orsubstituted C₁-C₃ alkanediyl (e.g., alkyl-substituted such as methyl ordimethyl), preferably C₁ alkanediyl (—CH₂—), C₃ alkanediyl (—(CH₂)₃—),or cycloalkanediyl, preferably cyclopropanediyl. In certain embodiments,R²¹ is:

In certain embodiments, R²² is selected from:

wherein R¹¹ to R¹⁴ are each individually H or alkyl, provided that atleast one of R¹¹ to R¹⁴ is alkyl. In certain embodiments, R¹² and R¹³are each alkyl (e.g., methyl) and R¹¹ and R¹⁴ are each H. In certainembodiments, R¹¹ and R¹⁴ are each alkyl (e.g., methyl) and R¹² and R¹³are each H.

In certain embodiments, R²² is a divalent radical of a N-heterocyclicgroup. Illustrative N-heterocylic groups include piperazinyl,substituted piperazinyl, azabicyclo (for example, azabicyclooctane), andsubstituted azabicyclo.

In certain embodiments, R²³ is selected from phenyl, substituted phenyl(e.g., alkyl-substituted phenyl such as dimethyl-substituted, or halogensubstituted, such as chloro- or fluoro-substituted, oramino-substituted, or aminoalkyl-substituted; alkynyl-substitutedphenyl), piperidinyl, substituted piperidinyl (e.g., amino-substituted),furanyl, substituted furanyl (e.g., aminoalkyl-substituted oramino-substituted), pyridinyl, substituted pyridinyl (e.g.,aminoalkyl-substituted or amino-substituted), pyrimidinyl, substitutedpyrimidinyl (e.g., aminoalkyl-substituted or amino-substituted),naphthenyl, substituted naphthenyl, (e.g., aminoalkyl-substituted oramino-substituted), thiazole, substituted thiazole (e.g.,aminoalkyl-substituted or amino-substituted); isoindazolyl, substitutedisoindazolyl (e.g., aminoalkyl-substituted or amino-substituted);triazolyl, or substituted triazolyl (e.g., aminoalkyl-substituted oramino-substituted). R²³ may have two or more substituents, such as analkyl substituent and a halogen substituent. Preferably, R²³ is asubstituted phenyl having a structure of:

wherein each of R¹-R⁵ is individually H, alkyl, substituted alkyl,alkynyl, substituted alkynyl, halogen, or cyano, provided that at leastone of R¹-R⁵ is not H. In certain embodiments, at least one of R¹-R⁵ isalkyl (such as methyl), halogen or cyano. In certain embodiments, R¹ isalkyl, halogen or cyano. In certain embodiments, R¹ is alkyl and R⁴ ishalogen. In certain embodiments, at least one of R¹-R⁵ ishydroxy-substituted alkynyl.

In certain embodiments, Z is selected from C₁-C₃ alkanediyl, preferably—CH₂—.

In certain embodiments, R²⁰ is phenyl or substituted isoxazolyl, b is 0;c is 1; a is 1; R²¹ is —CH₂—, Y is S; X is —S(═O)(═O)—, R²² is:

and R²³ is substituted phenyl.

In certain embodiments, R²⁰ is substituted phenyl, b is 0, c is 0, R²¹is cyclopropanediyl, a is 1, X is —C(═O)—, d is 1, R²² is

and R²³ is substituted phenyl. In one such embodiment, R²⁰ is halophenyland R²³ is halo- and alkyl-substituted phenyl.

In certain embodiments, R²¹ is —CH₂—, Y is S; and X is —S(═O)(═O)—.

In certain embodiments, R²² is:

In certain embodiments, Y is S, O, S(═O), —S(═O)(═O)—; and X is —C(═O)—.

In certain embodiments, b is 0; c is 0; a is 1; and X is —C(═O)—.

In certain embodiments, b is 0; c is 0; a is 1; X is —C(═O)—; and R²¹ isalkanediyl (particularly —CH₂CH₂—),

In certain embodiments, b is 0; c is 0; a is 1; X is —C(═O)—; R²¹ isalkanediyl (particularly —CH₂CH₂—),

and R²² is

In certain embodiments, b is 0; c is 0; a is 1; X is —C(═O)—; R²¹ isalkanediyl (particularly —CH₂CH₂—),

R²² is

R²⁰ is phenyl, substituted phenyl, or substituted isoxazolyl; and R²³ issubstituted phenyl.

In a further embodiment, the agent is a compound, or a pharmaceuticallyacceptable salt or ester thereof, having a formula II of:

R³⁰-(Z′)_(b)-(Y′)—(R³¹)_(a)—X′—R³²—R³³

wherein R³⁰ is an aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy,aryloxy, amino, a thio-containing group, or a seleno-containing group;

Z′ is alkanediyl, or substituted alkanediyl;

Y′ is S;

R³¹ is alkanediyl or substituted alkanediyl;

X is —C(═O)—;

R³² is a moiety that includes at least one divalent amino radical;

R³³ is a phenyl substituted with at least one halogen or cyano;

a is 0 or 1; and

b is 0 or 1.

In certain embodiments, R³⁰ is selected from isoxazolyl, substitutedisoxazolyl (e.g, dialkyl-substituted such as dimethyl,hydroxy-substituted, hydroxyalkyl-substituted, or a combinationthereof), oxazolyl, substituted oxazolyl (e.g, dialkyl-substituted suchas dimethyl, hydroxy-substituted, hydroxyalkyl-substituted, or acombination thereof) cyclohexyl, substituted cyclohexyl (e.g.,hydroxy-substituted cyclohexyl), piperidinyl, substituted piperidinyl(e.g., hydroxy-substituted piperidinyl), oxacyclopentyl, substitutedoxacyclopentyl (e.g., hydroxyalkyl-substituted), oxacyclohexanyl,substituted oxacyclopentyl (e.g., hydroxyalkyl-substituted), thiophenyl,substituted thiophenyl (e.g., hydroxyalkyl-substituted), phenyl,substituted phenyl (e.g., hydroxyalkyl-substituted), pyridinyl,substituted pyridinyl (e.g., hydroxyalkyl-substituted), indolyl,substituted indolyl (e.g., hydroxyalkyl-substituted), furanyl,substituted furanyl (e.g., hydroxyalkyl-substituted), imidazolyl,substituted imidazolyl (e.g., hydroxyalkyl-substituted). In preferredembodiments, R³⁰ is substituted isoxazolyl, particularly dialkyl (e.g.,dimethyl)-substituted isooxazolyl, or phenyl.

In certain embodiments, Z′ is selected from C₁-C₃ alkanediyl, preferably—CH₂—.

In certain embodiments, R³¹ is selected from C₁-C₃ alkanediyl orsubstituted C₁-C₃ alkanediyl (e.g., alkyl-substituted such as methyl ordimethyl), preferably C₁ alkanediyl.

In certain embodiments, R³² is selected from:

Preferably, R³³ is a substituted phenyl having a structure of:

wherein each of R¹-R⁵ is individually H, alkyl, halogen, or cyano,provided that at least one of R¹-R⁵ is halogen or cyano. In certainembodiments, R¹ is alkyl, halogen or cyano.

In certain embodiments, R³⁰ is substituted isoxazolyl, b is 1; a is 1;R²¹ is —CH₂—; and R³² is:

In a further embodiment, the agent is a compound, or stereoisomer,pharmaceutically acceptable salt, or an ester thereof according toformula III:

where the bond represented by “

” is a single or double bond. R²⁰ is (a) phenyl substituted with C₁-C₃perfluoroalkyl, halo, or pentafluorosulfanyl, (b) thiophenyl substitutedwith C₁-C₃ alkyl, or (c) cycloalkyl substituted with C₁-C₃perfluoroalkyl. R²³ is (a) phenyl mono- or di-substituted withsubstituents selected from halo, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl,pentafluorosulfanyl (—SF₅), cyano, —C(O)Oalkyl, or —C(O)N(H)alkyl (b)pyrimidinyl, (c) cycloalkyl, or (d) heterocycloalkyl. R²⁴ and R²⁵ areabsent if the bond represented by “

” is a double bond, or R²⁴ and R²⁵ independently are hydrogen,deuterium, C₁-C₃ perhaloalkyl, halo, or cyano, or R²⁴ and R²⁵ togetherform —CH₂—. R²⁶ and R²⁷ independently are hydrogen, deuterium, or halo.In some embodiments, when R²⁴-R²⁷ are hydrogen, then R²⁰ is nothalo-substituted phenyl.

In some examples, R²⁰ is phenyl substituted with —CF₃, —SF₅, or —F;thiophenyl substituted with —CH₃; or cyclohexyl substituted with —CF₃.In certain examples, R²⁰ is phenyl or cyclohexyl and is substituted atthe C4 position. In other examples, R²⁰ is phenyl substituted at the C3position.

In any of the foregoing examples, R²³ may be phenyl substituted with—CF₃; phenyl disubstituted with two halo substituents, halo and —CF₃,halo and —CH₃, or halo and cyano; pyrimidinyl; cyclohexyl; orheterocyclohexyl (e.g., containing a heteroatom or group selected fromO, N(H), or N(CH₃)). In some examples, R²³ is a disubstituted phenyl andthe two substituents are para to one another.

In certain embodiments, the compound, or a stereoisomer,pharmaceutically acceptable salt, or ester thereof, has a formulaaccording to any one of formulas IV-XVII:

wherein R²⁰ is phenyl substituted with C₁-C₃ perfluoroalkyl, halo, orpentafluorosulfanyl; R²⁴-R²⁷ independently are hydrogen, deuterium, orhalo; R²⁸ is O, N(CH₃), or CH₂; R²⁹ is N, O, or S; R³⁰ is CH or N; eachR³¹ independently is C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, halo,pentafluorosulfanyl, —C(O)Oalkyl, or C(O)N(H)alkyl; and q is 1, 2, or 3.

In any or all embodiments, R²⁰ may be phenyl substituted with —CF₃,—SF₅, or —F. In some embodiments, R²⁰ is substituted at the C3 or C4position. In any or all embodiments, each R³¹ independently may be C₁-C₃alkyl, C₁-C₃ perfluoroalkyl, or halo. In any or all embodiments, eachR³¹ independently may be methyl, trifluoromethyl, or chloro. In any ofthe foregoing embodiments, q may be 2, and the R³¹ substituents are parato one another.

Illustrative compounds are shown in FIGS. 1A-1D and 2A-2J. With respectto FIG. 2A-2J, each R independently is C₁-C₃ perfluoroalkyl, halo,pentafluorosulfanyl, —C(O)Oalkyl, or C(O)N(H)alkyl.

FIG. 4 shows a synthesis of a parent structure that is amenable to themodifications lined out in a zone model. Isoxazole 2a can be obtainedfrom the chloromethylation of 3,5-dimethylisoxazole, or via thecorresponding alcohol, and can be converted to thiol 2b. In situalkylation of 2b with chloride 2d under the basic conditions of thiolateformation leads to 1. There are many methods known for pyridazinesynthesis, and the preparation of 2c can follow one of these methods,for example starting with the aniline. Acylation of 2c with chloroacetylchloride provides 2d. FIG. 5 shows zones of modification for compound 1.The building blocks for zones 1 and 4 have been selected to cover alarge range of chemical diversity; in addition, they are commerciallyavailable and are therefore readily funneled into the segment-basedsynthesis plan. Zone 2 contains a few diamines that preserve thedistance between zone 1 and zone 3, i.e. where the nitrogens areappropriately spaced, but this zone can also be contracted to a simplenitrogen linker in order to probe the need to maintain the overalldistance and orientation between zone 1 and zone 4. Zone 3 containsanother spacer functionality, but the amide carbonyl group might also beinvolved in specific interactions with the binding site on the protein.Therefore, the distance between the carboxyl function and the halideelectrophile can be varied, and the carbonyl group can also be replacedby a sulfonyl function.

As described below, compounds 5a-h were synthesized directly fromcommercially available carboxylic acids 3a and N-arylated piperazines4a-h under amide coupling conditions with T3P (Scheme 1 (FIG. 6) andTable 1) (Basavaprabhhu et al., Synthesis 2013, 45, 1569-1601). Thediamine linker in zone 2 was examined in more detail through thesynthesis of analogs 5i-5m. For these target molecules, the requisitediamines 4i-m were prepared by a Buchwald-Hartwig cross-coupling of monoBoc-protected diamines with bromoarenes (Cabello-Sanchez et al., J. Org.Chem. 2007, 72, 2030-2039; Larsen et al., Tetrahedron 2008, 64,2938-2950). Reduction of amide 5b with lithium aluminum hydride led todiamine 6. For an initial set of zone 4 analogs, thioether 5b was alsooxidized to sulfoxide 12 and sulfone 13 in good yields with sodiumperiodate and m-chloroperbenzoate, respectively (Scheme 1, FIG. 6).

Additional zone 4 and zone 5 analogs with a phenyl group in place of theisoxazole ring were obtained from carboxylic acids 3b-3g (Scheme 2 (FIG.7) and Table 1). Coupling to piperazine 4b provided amides 7-11 and 16in high yields. Alkynyl amide 10 was further hydrogenated to cis-alkene14 using a Lindlar catalyst. The cis-cyclopropane 15 was prepared by aSimmons-Smith cyclopropanation of cis-alkene 14 (Concellón et al., Org.Lett. 2007, 9, 2981-2984), whereas the trans-cyclopropane 16 wasobtained by coupling of commercially availabletrans-2-phenylcyclopropanecarboxylic acid 3g with piperazine 4b.

Further modifications in zones 3-4 were accomplished by acylation ofpiperazine 4b with either 2-chloroacetyl chloride orchloromethanesulfonyl chloride to form the corresponding amide 17a orsulfonamide 17b in good yields (Scheme 3 (FIG. 8) and Table 1).S_(N)2-reaction of 17a and 17b led to ether 18a, amine 18b, andthioether 18c. Starting with carboxylic acid 3a, urea 20a and carbamate20b were obtained in moderate yields via a Curtius rearrangement andaddition of the intermediate isocyanate 19 to amine 4b and alcohol 4n,respectively (Scheme 3, FIG. 8) (WO 2005/085275).

A bridged bicyclic ring was introduced to add a strong conformationalconstraint in zone 2 (Scheme 4 (FIG. 9) and Table 1). Boc-protection ofnortropinone hydrochloride 21 followed by enolization with NaHMDS andtrapping of the enolate with N-phenyltriflimide provided vinyl triflate22 in good yield. A Suzuki coupling was used to install the o-tolylgroup, and the styrene double bond was reduced with Pd/C to afford 23 asa mixture of diastereomers. Without separation, this mixture wasdeprotected and acylated with a-chloroacetyl chloride. Finally, thechloride was displaced using thiol 25 and sodium hydride to afford thethioether. Diastereomers 26a and 26b were separated by chromatography onSiO₂ to afford both analogs in modest yields.

TABLE 1 Structures of amine building blocks 4 and analogs 5, 7-11, and16. Analog Amine 4 R X  5a

Ph —  5b

(2-Me)Ph —  5c

(3-Me)Ph —  5d

(4-Me)Ph —  5e

(2-NC)Ph —  5f

(2-F)Ph —  5g

1-Naphthyl —  5h

(2-MeO)Ph —  5i

(2-Me)Ph —  5j

(2-Me)Ph —  5k

(2-Me)Ph —  5l

Ph —  5m

(3-Me)Ph —  7

(2-Me)Ph CH₂SCH₂  8

(2-Me)Ph (CH₂)₃  9

(2-Me)Ph SCH₂ 10

(2-Me)Ph C≡C 11

(2-Me)Ph (E)-HC═CH 16

(2-Me)Ph (E)-c-C₃H₄

Pharmaceutical Compositions and Method of Use

The agents disclosed herein may be administered to a subject fortreating prostate cancer, particularly castration-resistant prostatecancer. In certain embodiments a subject is identified as havingcastration-resistant prostate cancer that may be responsive to theagents disclosed herein. For example, patients that are offered any formof androgen deprivation therapy or anti-androgen therapy, includingtreatment with abiraterone or MDV3100, for the management of prostatecancer would be candidates for treatment with the agents disclosedherein.

Administration of the agent may reduce the nuclear level of androgenreceptor in castration-resistant prostate cancer (CRPC) cells relativeto the untreated control CRPC cells. Reducing nuclear androgen receptorlevels is expected to inhibit its activation. Reduction of androgenreceptor activation can be determined via measuring androgen-responsivegenes, such as prostate-specific antigen (PSA).

In certain embodiments, the agent may be co-administered with anothertherapeutic agent such as, for example, an immunostimulant, ananti-cancer agent, an antibiotic, or a combination thereof. Inparticular, the agents targeting AR nuclear localization could be usedin combination with standard androgen deprivation therapy (ADT) or withabiratrone in the treatment of CRPC. In one embodiment, the agent isco-administered with MDV3100 (enzalutamide), which may producesynergistic results since MDV3100 targets the ligand binding domainwhereas the agent targets other domain(s) of the androgen receptor.

The agents disclosed herein can be included in a pharmaceuticalcomposition for administration to a subject. The pharmaceuticalcompositions for administration to a subject can include at least onefurther pharmaceutically acceptable additive such as carriers,thickeners, diluents, buffers, preservatives, surface active agents andthe like in addition to the molecule of choice. Pharmaceuticalcompositions can also include one or more additional active ingredientssuch as antimicrobial agents, anti-inflammatory agents, anesthetics, andthe like. The pharmaceutically acceptable carriers useful for theseformulations are conventional. Remington's Pharmaceutical Sciences, byE. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition (1995),describes compositions and formulations suitable for pharmaceuticaldelivery of the compounds herein disclosed.

The pharmaceutical compositions may be in a dosage unit form such as aninjectable fluid, an oral delivery fluid (e.g., a solution orsuspension), a nasal delivery fluid (e.g., for delivery as an aerosol orvapor), a semisolid form (e.g., a topical cream), or a solid form suchas powder, pill, tablet, or capsule forms.

In general, the nature of the carrier will depend on the particular modeof administration being employed. For instance, parenteral formulationsusually contain injectable fluids that include pharmaceutically andphysiologically acceptable fluids such as water, physiological saline,balanced salt solutions, aqueous dextrose, glycerol or the like as avehicle. For solid compositions (for example, powder, pill, tablet, orcapsule forms), conventional non-toxic solid carriers can include, forexample, pharmaceutical grades of mannitol, lactose, starch, ormagnesium stearate. In addition to biologically-neutral carriers,pharmaceutical compositions to be administered can contain minor amountsof non-toxic auxiliary substances, such as wetting or emulsifyingagents, preservatives, and pH buffering agents and the like, for examplesodium acetate or sorbitan monolaurate.

The agents disclosed herein can be administered to subjects by a varietyof mucosal administration modes, including by oral, rectal, intranasal,intrapulmonary, or transdermal delivery, or by topical delivery to othersurfaces. Optionally, the agents can be administered by non-mucosalroutes, including by intramuscular, subcutaneous, intravenous,intra-arterial, intra-articular, intraperitoneal, intrathecal,intracerebroventricular, or parenteral routes. In other alternativeembodiments, the agents can be administered ex vivo by direct exposureto cells, tissues or organs originating from a subject.

To formulate the pharmaceutical compositions, the agents can be combinedwith various pharmaceutically acceptable additives, as well as a base orvehicle for dispersion of the compound. Desired additives include, butare not limited to, pH control agents, such as arginine, sodiumhydroxide, glycine, hydrochloric acid, citric acid, and the like. Inaddition, local anesthetics (for example, benzyl alcohol), isotonizingagents (for example, sodium chloride, mannitol, sorbitol), adsorptioninhibitors (for example, Tween 80 or Miglyol 812), solubility enhancingagents (for example, cyclodextrins and derivatives thereof), stabilizers(for example, serum albumin), and reducing agents (for example,glutathione) can be included. Adjuvants, such as aluminum hydroxide (forexample, Amphogel, Wyeth Laboratories, Madison, N.J.), Freund'sadjuvant, MPL™ (3-O-deacylated monophosphoryl lipid A; Corixa, Hamilton,Ind.) and IL-12 (Genetics Institute, Cambridge, Mass.), among many othersuitable adjuvants well known in the art, can be included in thecompositions. When the composition is a liquid, the tonicity of theformulation, as measured with reference to the tonicity of 0.9% (w/v)physiological saline solution taken as unity, is typically adjusted to avalue at which no substantial, irreversible tissue damage will beinduced at the site of administration. Generally, the tonicity of thesolution is adjusted to a value of about 0.3 to about 3.0, such as about0.5 to about 2.0, or about 0.8 to about 1.7.

The agents can be dispersed in a base or vehicle, which can include ahydrophilic compound having a capacity to disperse the compound, and anydesired additives. The base can be selected from a wide range ofsuitable compounds, including but not limited to, copolymers ofpolycarboxylic acids or salts thereof, carboxylic anhydrides (forexample, maleic anhydride) with other monomers (for example, methyl(meth)acrylate, acrylic acid and the like), hydrophilic vinyl polymers,such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone,cellulose derivatives, such as hydroxymethylcellulose,hydroxypropylcellulose and the like, and natural polymers, such aschitosan, collagen, sodium alginate, gelatin, hyaluronic acid, andnontoxic metal salts thereof. Often, a biodegradable polymer is selectedas a base or vehicle, for example, polylactic acid, poly(lacticacid-glycolic acid) copolymer, polyhydroxybutyric acid,poly(hydroxybutyric acid-glycolic acid) copolymer and mixtures thereof.Alternatively or additionally, synthetic fatty acid esters such aspolyglycerin fatty acid esters, sucrose fatty acid esters and the likecan be employed as vehicles. Hydrophilic polymers and other vehicles canbe used alone or in combination, and enhanced structural integrity canbe imparted to the vehicle by partial crystallization, ionic bonding,cross-linking and the like. The vehicle can be provided in a variety offorms, including fluid or viscous solutions, gels, pastes, powders,microspheres and films for direct application to a mucosal surface.

The agents can be combined with the base or vehicle according to avariety of methods, and release of the agents can be by diffusion,disintegration of the vehicle, or associated formation of waterchannels. In some circumstances, the agent is dispersed in microcapsules(microspheres) or nanocapsules (nanospheres) prepared from a suitablepolymer, for example, isobutyl 2-cyanoacrylate (see, for example,Michael et al., J. Pharmacy Pharmacol. 43:1-5, 1991), and dispersed in abiocompatible dispersing medium, which yields sustained delivery andbiological activity over a protracted time.

The compositions of the disclosure can alternatively contain aspharmaceutically acceptable vehicles substances as required toapproximate physiological conditions, such as pH adjusting and bufferingagents, tonicity adjusting agents, wetting agents and the like, forexample, sodium acetate, sodium lactate, sodium chloride, potassiumchloride, calcium chloride, sorbitan monolaurate, and triethanolamineoleate. For solid compositions, conventional nontoxic pharmaceuticallyacceptable vehicles can be used which include, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate, and the like.

Pharmaceutical compositions for administering the agents can also beformulated as a solution, microemulsion, or other ordered structuresuitable for high concentration of active ingredients. The vehicle canbe a solvent or dispersion medium containing, for example, water,ethanol, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like), and suitable mixtures thereof.Proper fluidity for solutions can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of a desired particlesize in the case of dispersible formulations, and by the use ofsurfactants. In many cases, it will be desirable to include isotonicagents, for example, sugars, polyalcohols, such as mannitol andsorbitol, or sodium chloride in the composition. Prolonged absorption ofthe compound can be brought about by including in the composition anagent which delays absorption, for example, monostearate salts andgelatin.

In certain embodiments, the agents can be administered in a time releaseformulation, for example in a composition which includes a slow releasepolymer. These compositions can be prepared with vehicles that willprotect against rapid release, for example a controlled release vehiclesuch as a polymer, microencapsulated delivery system or bioadhesive gel.Prolonged delivery in various compositions of the disclosure can bebrought about by including in the composition agents that delayabsorption, for example, aluminum monostearate hydrogels and gelatin.When controlled release formulations are desired, controlled releasebinders suitable for use in accordance with the disclosure include anybiocompatible controlled release material which is inert to the activeagent and which is capable of incorporating the compound and/or otherbiologically active agent. Numerous such materials are known in the art.Useful controlled-release binders are materials that are metabolizedslowly under physiological conditions following their delivery (forexample, at a mucosal surface, or in the presence of bodily fluids).Appropriate binders include, but are not limited to, biocompatiblepolymers and copolymers well known in the art for use in sustainedrelease formulations. Such biocompatible compounds are non-toxic andinert to surrounding tissues, and do not trigger significant adverseside effects, such as nasal irritation, immune response, inflammation,or the like. They are metabolized into metabolic products that are alsobiocompatible and easily eliminated from the body.

Exemplary polymeric materials for use in the present disclosure include,but are not limited to, polymeric matrices derived from copolymeric andhomopolymeric polyesters having hydrolyzable ester linkages. A number ofthese are known in the art to be biodegradable and to lead todegradation products having no or low toxicity. Exemplary polymersinclude polyglycolic acids and polylactic acids, poly(DL-lacticacid-co-glycolic acid), poly(D-lactic acid-co-glycolic acid), andpoly(L-lactic acid-co-glycolic acid). Other useful biodegradable orbioerodable polymers include, but are not limited to, such polymers aspoly(epsilon-caprolactone), poly(epsilon-caprolactone-CO-lactic acid),poly(epsilon.-caprolactone-CO-glycolic acid), poly(beta-hydroxy butyricacid), poly(alkyl-2-cyanoacrilate), hydrogels, such as poly(hydroxyethylmethacrylate), polyamides, poly(amino acids) (for example, L-leucine,glutamic acid, L-aspartic acid and the like), poly(ester urea),poly(2-hydroxyethyl DL-aspartamide), polyacetal polymers,polyorthoesters, polycarbonate, polymaleamides, polysaccharides, andcopolymers thereof. Many methods for preparing such formulations arewell known to those skilled in the art (see, for example, Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978). Other useful formulations includecontrolled-release microcapsules (U.S. Pat. Nos. 4,652,441 and4,917,893), lactic acid-glycolic acid copolymers useful in makingmicrocapsules and other formulations (U.S. Pat. Nos. 4,677,191 and4,728,721) and sustained-release compositions for water-soluble peptides(U.S. Pat. No. 4,675,189).

The pharmaceutical compositions of the disclosure typically are sterileand stable under conditions of manufacture, storage and use. Sterilesolutions can be prepared by incorporating the compound in the requiredamount in an appropriate solvent with one or a combination ofingredients enumerated herein, as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thecompound and/or other biologically active agent into a sterile vehiclethat contains a basic dispersion medium and the required otheringredients from those enumerated herein. In the case of sterilepowders, methods of preparation include vacuum drying and freeze-dryingwhich yields a powder of the compound plus any additional desiredingredient from a previously sterile-filtered solution thereof. Theprevention of the action of microorganisms can be accomplished byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

In accordance with the various treatment methods of the disclosure, theagent can be delivered to a subject in a manner consistent withconventional methodologies associated with management of the disorderfor which treatment or prevention is sought. In accordance with thedisclosure herein, a prophylactically or therapeutically effectiveamount of the agent is administered to a subject in need of suchtreatment for a time and under conditions sufficient to prevent,inhibit, and/or ameliorate a selected disease or condition or one ormore symptom(s) thereof.

The administration of the agent can be for either prophylactic ortherapeutic purpose. When provided prophylactically, the agent isprovided in advance of any symptom. The prophylactic administration ofthe agents serves to prevent or ameliorate any subsequent diseaseprocess. When provided therapeutically, the compound is provided at (orshortly after) the onset of a symptom of disease or infection.

For prophylactic and therapeutic purposes, the agent can be administeredto the subject by the oral route or in a single bolus delivery, viacontinuous delivery (for example, continuous transdermal, mucosal orintravenous delivery) over an extended time period, or in a repeatedadministration protocol (for example, by an hourly, daily or weekly,repeated administration protocol). The therapeutically effective dosageof the agent can be provided as repeated doses within a prolongedprophylaxis or treatment regimen that will yield clinically significantresults to alleviate one or more symptoms or detectable conditionsassociated with a targeted disease or condition as set forth herein.Determination of effective dosages in this context is typically based onanimal model studies followed up by human clinical trials and is guidedby administration protocols that significantly reduce the occurrence orseverity of targeted disease symptoms or conditions in the subject.Suitable models in this regard include, for example, murine, rat, avian,porcine, feline, non-human primate, and other accepted animal modelsubjects known in the art. Alternatively, effective dosages can bedetermined using in vitro models. Using such models, only ordinarycalculations and adjustments are required to determine an appropriateconcentration and dose to administer a therapeutically effective amountof the compound (for example, amounts that are effective to elicit adesired immune response or alleviate one or more symptoms of a targeteddisease). In alternative embodiments, an effective amount or effectivedose of the agents may simply inhibit or enhance one or more selectedbiological activities correlated with a disease or condition, as setforth herein, for either therapeutic or diagnostic purposes.

The actual dosage of the agents will vary according to factors such asthe disease indication and particular status of the subject (forexample, the subject's age, size, fitness, extent of symptoms,susceptibility factors, and the like), time and route of administration,other drugs or treatments being administered concurrently, as well asthe specific pharmacology of the agent for eliciting the desiredactivity or biological response in the subject. Dosage regimens can beadjusted to provide an optimum prophylactic or therapeutic response. Atherapeutically effective amount is also one in which any toxic ordetrimental side effects of the agent is outweighed in clinical terms bytherapeutically beneficial effects. A non-limiting range for atherapeutically effective amount of an agent within the methods andformulations of the disclosure is about 0.01 mg/kg body weight to about20 mg/kg body weight, such as about 0.05 mg/kg to about 5 mg/kg bodyweight, or about 0.2 mg/kg to about 2 mg/kg body weight. Dosage can bevaried by the attending clinician to maintain a desired concentration ata target site (for example, the lungs or systemic circulation). Higheror lower concentrations can be selected based on the mode of delivery,for example, trans-epidermal, rectal, oral, pulmonary, or intranasaldelivery versus intravenous or subcutaneous delivery. Dosage can also beadjusted based on the release rate of the administered formulation, forexample, of an intrapulmonary spray versus powder, sustained releaseoral versus injected particulate or transdermal delivery formulations,and so forth.

Certain embodiments are described below in the following numberedclauses:

1. A compound, or a stereoisomer, pharmaceutically acceptable salt, orester thereof, selected from:

(i) a compound according to formula III

where the bond represented by “

” is a single or double bond; R²⁰ is (a) phenyl substituted with C₁-C₃perfluoroalkyl, halo, or pentafluorosulfanyl, (b) thiophenyl substitutedwith C₁-C₃ alkyl, or (c) cycloalkyl substituted with C₁-C₃perfluoroalkyl; R²³ is (a) phenyl mono- or di-substituted withsubstituents selected from halo, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl,pentafluorosulfanyl, cyano, —C(O)Oalkyl, or —C(O)N(H)alkyl (b)pyrimidinyl, (c) cycloalkyl, or (d) heterocycloalkyl; R²⁴ and R²⁵ areabsent if the bond represented by “

” is a double bond, or R²⁴ and R²⁵ independently are hydrogen,deuterium, C₁-C₃ perhaloalkyl, halo, or cyano, or R²⁴ and R²⁵ togetherform —CH₂—; and R²⁶ and R²⁷ independently are hydrogen, deuterium, orhalo, wherein if R²⁴-R²⁷ are hydrogen, then R²⁰ is not halo-substitutedphenyl; or

(ii) a compound in Table A, where each R independently is C₁-C₃perfluoroalkyl, halo, pentafluorosulfanyl, —C(O)Oalkyl, orC(O)N(H)alkyl, R²⁸ is O, N(CH₃), or CH₂, R²⁹ is N, O, or S, and R³⁰ isCH or N

TABLE A

2. The compound of clause 1, wherein R²⁰ is: phenyl substituted with—CF₃, —SF₅, or —F; thiophenyl substituted with —CH₃; or cyclohexylsubstituted with —CF₃.

3. The compound of clause 2, wherein R²⁰ is phenyl or cyclohexyl and issubstituted at the C4 position.

4. The compound of any one of clauses 1-3, wherein R²³ is: phenylsubstituted with —CF₃; phenyl disubstituted with two halo substituents,halo and —CF₃, halo and —CH₃, or halo and cyano; pyrimidinyl;cyclohexyl; or heterocyclohexyl.

5. The compound of clause 4, wherein R²³ is disubstituted phenyl and thetwo substituents are para to one another.

6. The compound of clause 1, wherein the compound is:

7. The compound of clause 1, wherein the compound is:

8. The compound of clause 1, wherein the compound is:

9. The compound of clause 1, wherein the compound is:

10. A pharmaceutical composition comprising at least onepharmaceutically acceptable additive, and a compound of any one ofclauses 1-9.

11. The pharmaceutical composition of clause 10, wherein the compound isa compound recited in clause 6.

12. The pharmaceutical composition of clause 10, wherein the compoundis:

13. The pharmaceutical composition of clause 10, wherein the compoundis:

14. The pharmaceutical composition of clause 10, wherein the compound isa compound recited in clause 9.

15. A method for treating prostate cancer in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of any one of clauses 1-9.

16. The method of clause 15, wherein the prostate cancer iscastration-resistant prostate cancer.

17. The method of clause 15 or clause 16, wherein the compound is orallyadministered.

18. The method of any one of clauses 15-17, wherein the method is usedin combination with androgen deprivation therapy.

19. The method of any one of clauses 15-18, wherein the agent isco-administered with abiratrone.

20. The method of any one of clauses 15-18, wherein the agent isco-administered with enzalutamide.

21. The method of any one of clauses 15-20, wherein the method furthercomprises identifying a subject that is in need of treatment with theagent.

22. The method of any one of clauses 15-21, wherein the compound is acompound recited in clause 6.

23. The method of any one of clauses 15-21 wherein the compound is:

24. The method of any one of clauses 15-21, wherein the compound is:

25. The method of any one of clauses 15-21, wherein the compound is acompound recited in clause 9.

EXAMPLES 1. Biological Materials and Methods Materials

Phosphate buffered saline (PBS) solution was purchased from FisherScientific (MA, USA). Trypsin-EDTA solution, dimethyl sulfoxide (DMSO),Roswell Park Memorial Institute (RPMI) 1640 medium, ethanol (200 proof),puromycin powder, and G418 powder were purchased from Sigma-Aldrich (MO,USA). Fetal bovine Serum (FBS), penicillin-streptomycin solution werepurchased from Invitrogen (NY, USA). Dual-Luciferase® Reporter AssaySystem was purchased from Promega (WI, USA). PSA6.1-luc plasmid was agift from Dr. Marianne Sadar at the University of British Columbia (BC,CA) and pRL-TK Renilla luciferase reporter plasmid was purchased fromPromega (WI, USA). The C4-2 castration-resistant prostate cancer cellline was kindly provided by Dr. Leland W.K. Chung (Cedars-Sinai MedicalCenter).

2. Chemistry General

Moisture and air-sensitive reactions were performed under N₂ or Aratmosphere and glassware used for these reactions was flamed dried andcooled under N₂ or Ar prior to use. THF and Et₂O were distilled fromsodium/benzophenone ketyl. DMF and CH₂Cl₂ were distilled from CaH₂.1,4-Dioxane was purchased from Acros (Sure/Seal bottle) and used asreceived. Et₃N was distilled from CaH₂ and stored over KOH. Toluene waspurified by passage through an activated alumina filtration system.Melting points were determined using a Mel-Temp II instrument and arenot corrected. Infrared spectra were determined using a Smiths DetectionIdentifyIR FT-IR spectrometer. High-resolution mass spectra wereobtained on a Micromass UK Limited, Q-TOF Ultima API, Thermo ScientificExactive Orbitrap LC-MS. Automated column chromatography was done usingan Isco Combiflash Rf. ¹H and ¹³C NMR spectra were obtained on BrukerAdvance 300 MHz, 400 MHz, or 500 MHz instruments. Chemical shifts (δ)were reported in parts per million with the residual solvent peak usedas an internal standard, δ ¹H/¹³C (Solvent): 7.26/77.00 (CDCl₃);2.05/29.84 (acetone-d6); 2.50/39.52 (DMSO-d6), 3.31/49.00 (CD₃OD); andare tabulated as follows: chemical shift, multiplicity (s=singlet,brs=broad singlet, d=doublet, brd=broad doublet, t=triplet, appt=apparent triplet, q=quartet, m=multiplet), number of protons, andcoupling constant(s). ¹³C NMR spectra were obtained at 75 MHz, 100 MHz,or 125 MHz using a proton-decoupled pulse sequence and are tabulated byobserved peak. CDCl₃ was filtered through dried basic alumina prior touse. Thin-layer chromatography was performed using pre-coated silica gel60 F₂₅₄ plates (EMD, 250 μm thickness) and visualization wasaccomplished with a 254 nm UV light and by staining with a PMA solution(5 g of phosphomolybdic acid in 100 mL of 95% EtOH), Vaughn's reagent(4.8 g of (NH₄)₆Mo₇O₂₄.4H₂O and 0.2 g of Ce(SO₄)₂ in 100 mL of a 3.5 NH₂SO₄ solution) or a KMnO₄ solution (1.5 g of KMnO₄ and 1.5 g of K₂CO₃in 100 mL of a 0.1% NaOH solution). Chromatography on SiO₂ (Silicycle,Silia-P Flash Silica Gel or SiliaFlash® P60, 40-63 μm) was used topurify crude reaction mixtures. Final products were >95% purity asanalyzed by RP (reverse phase) HPLC (Alltech Prevail C-18, 100×4.6 mm, 1mL/min, CH₃CN, H₂O and 0.1% TFA) with UV (210, 220 and 254 nm), ELS(nebulizer 45° C., evaporator 45° C., N₂ flow 1.25 SLM), and MSdetection using a Thermo Scientific Exactive Orbitrap LC-MS (ESIpositive). All other materials were obtained from commercial sources andused as received.

Example 1 Synthesis and Characterization

Synthesis of several of the compounds is described in detail below:

tert-Butyl 4-(3-bromo-2-methylphenyl)piperazine-1-carboxylate(BRE454-64). A microwave vial under Ar was charged with tert-butyl1-piperazinecarboxylate (154 mg, 0.825 mmol), NaO-t-Bu (0.0952 g, 0.990mmol), (rac)-BINAP (0.0393 g, 0.0619 mmol, 7.5 mol %), Pd₂(dba)₃ (0.0192g, 0.0206 mmol), and degassed toluene (2.1 mL). 2-Bromo-6-iodotoluene(121 gL, 0.825 mmol) was added, and the mixture was heated in sealedvial at 80° C. for 19 h, cooled to room temperature, diluted withCH₂Cl₂, filtered through Celite, and concentrated in vacuo. The mixturewas purified by chromatography on SiO₂ (1:9, EtOAc/hexanes) to give theproduct (0.095 g, 0.27 mmol, 32%) as a yellow oil: ¹H NMR (500 MHz,CDCl₃) δ 7.30 (d, J=8.0 Hz, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.95 (d, J=7.5Hz, 1H), 3.57 (m, 4H), 2.83 (t, J=4.5 Hz, 4H), 2.40 (s, 3H), 1.49 (s,9H).

1-(4-(3-Bromo-2-methylphenyl)piperazin-1-yl)-2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)ethan-1-one (BRE454-75). A solution of BRE454-64 (0.0770 g, 0.22 mmol)in THF (0.3 mL) at 0° C. was treated with 4 M HCl in dioxane (1.3 mL)and stirred at 0° C. for 2 h. The yellow solid was collected byfiltration, washed with Et₂O, dried under high vacuum and carried on tothe next step without further purification.

To a solution of ([(3,5-dimethylisoxazol-4-yl)methyl]thio)acetic acid(0.0350 g, 0.174 mmol) in CH₂Cl₂ (1.7 mL) was added4-(3-bromo-2-methylphenyl)piperazine hydrochloride and triethylamine(121 μL, 0.870 mmol). The mixture was cooled to 0° C., treated with T3P(50% solution in EtOAc, 184 μL, 0.261 mmol), warmed to room temperature,stirred for 20 h, diluted with CH₂Cl₂, and washed with sat. NH₄Cl, sat.NaHCO₃, and brine. The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by chromatographyon SiO₂ (3:2, EtOAc/hexanes, base washed with 0.1% Et₃N prior to use) togive the product (0.0762 g, 0.174 mmol, quant. 100% pure by ELSD) as acolorless oil: IR (ATR) 2921, 2820, 1637, 1587, 1562, 1460, 1428, 1282,1237, 1195, 1136, 1038, 994, 913, 780, 731, 714 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 7.32 (dd, J=0.8, 7.6 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.94 (dd,J=0.8, 8.0 Hz, 1H), 3.77 (br s, 2H), 3.63 (s, 2H), 3.63-3.57 (m, 2H),3.23 (s, 2H), 2.90 (t, J=4.4 Hz, 2H), 2.88-2.83 (m, 2H), 2.43 (s, 3H),2.40 (s, 3H), 2.31 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ 167.6, 166.8,159.7, 152.2, 132.9, 128.1, 127.4, 126.6, 118.3, 109.7, 52.1, 51.8,46.8, 42.2, 32.1, 23.8, 18.2, 11.1, 10.2; HRMS (ESI) m/z calcd forC₁₉H₂₅N₃O₂BrS ([M+H]⁺) 438.0845, found 438.0831.

tert-Butyl 4-(o-tolyl)-1,4-diazepane-1-carboxylate (BRE454-66). Amicrowave vial under Ar was charged with 1-Boc-homopiperazine (223 mg,1.10 mmol), NaO-t-Bu (0.116 g, 1.20 mmol), (rac)-BINAP (0.0478 g, 0.0752mmol, 7.5% mol), Pd₂(dba)₃ (0.0233 g, 0.0251 mmol, 2.5% mol in Pd), anddegassed toluene (2.8 mL). 2-Bromotoluene (0.175 g, 1.00 mmol) wasadded, and the mixture was heated in a sealed vial at 80° C. for 19 h,cooled to room temperature diluted with CH₂Cl₂, filtered over Celite,and concentrated. The crude material was purified by chromatography onSiO₂ (1:9, EtOAc/hexanes) to give the product (0.139 g, 0.479 mmol, 48%)as a yellow oil: IR (ATR) 2973, 2828, 1689, 1598, 1491, 1457, 1411,1364, 1233, 1215, 1156, 1122, 878, 761, 725 cm⁻¹; ¹H NMR (500 MHz,CDCl₃, rt, rotamers) δ 7.16 (d, J=6.0 Hz, 1H), 7.12 (d, J=6.0 Hz, 1H),7.04 (d, J=7.5 Hz, 1H), 6.95 (t, J=7.0 Hz, 1H), 3.62-3.52 (m, 4H),3.12-3.04 (m, 4H), 2.31 (s, 3H), 2.00-1.88 (m, 2H), 1.49 (s, 9H);¹³C-NMR (100 MHz, CDCl₃, rt, rotamers) δ 155.6, 155.5, 153.9, 153.8,132.9, 130.9, 126.5, 123.1, 120.8 (2 C), 79.3, 56.2, 56.0, 55.5, 55.2,48.4, 48.0, 46.2, 45.4, 29.0, 28.9, 28.5, 18.5; HRMS (ESI) m/z calcd forC₁₇H₂₇N₂O₂ ([M+H]⁺) 291.2067, found 291.2062.

1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-2-4(3,5-dimethylisoxazol-4-yl)methyl)thio)ethan-1-one (BRE454-58). To a solution of([(3,5-dimethylisoxazol-4-yl)methyl]thio)acetic acid (0.0450 g, 0.224mmol) in CH₂Cl₂ (2.2 mL) was added 1-(5-chloro-2-methylphenyl)piperazine(0.0565 g, 0.268 mmol) and triethylamine (93 μL, 0.671 mmol). Themixture was cooled to 0° C., treated with T3P (50% solution in EtOAc,237 μL, 0.335 mmol), warmed to room temperature, stirred for 20 h,diluted with CH₂Cl₂, and washed with sat. NH₄Cl, sat. NaHCO₃, and brine.The organic layer was dried (Na₂SO₄), filtered, and concentrated invacuo. The crude material was purified by chromatography on SiO₂ (1:1,EtOAc/hexanes, base washed with 0.1% Et₃N prior to use) to give theproduct (0.0881 g, 0.224 mmol, quant, 99.9% pure by ELSD) as a clearcolorless oil: IR (ATR) 2921, 2818, 1635, 1592, 1489, 1438, 1270, 1224,1195, 1148, 1039, 924, 910, 818, 728 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.11 (d, J=8.0 Hz, 1H), 6.99 (dd, J=2.0, 8.0 Hz, 1H), 6.94 (d, J=2.4 Hz,1H), 3.76 (t, J=4.8 Hz, 2H), 3.63 (s, 2H), 3.59 (t, J=4.8 Hz, 2H), 3.23(s, 2H), 2.91 (t, J=4.8 Hz, 2H), 2.86 (t, J=4.8 Hz, 2H), 2.43 (s, 3H),2.30 (s, 3H), 2.27 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.6, 166.8,159.7, 151.7, 132.1, 131.8, 130.9, 123.7, 119.7, 109.7, 51.6, 51.5,46.8, 42.2, 32.0, 23.7, 17.4, 11.1, 10.2; HRMS (ESI) m/z calcd forC₁₉H₂₅N₃O₂ClS ([M+H]⁺) 394.1351, found 394.1340.

1-(((Phenylthio)methyl)sulfonyl)-4-(o-tolyl)piperazine (BRE454-84). Asolution of 1-(2-methylphenyl)piperazine (0.500 g, 2.75 mmol) andtriethylamine (0.39 mL, 2.75 mmol) in CH₂Cl₂ (9.8 mL) at 0° C. wastreated with chloromethanesulfonyl chloride (0.460 g, 3.03 mmol),gradually warmed to room temperature, and stirred for 14 h. The reactionmixture was quenched with sat. NH₄Cl (3 mL) and extracted with EtOAc(3×20 mL). The combined organic portion was washed with water (2×10 mL)and brine (10 mL), dried (Na₂SO₄), filtered, and concentrated. The crudesolid was filtered through a plug of SiO₂ (pretreated with 0.1% Et₃N in30% EtOAc/hexanes) and washed thoroughly with 30% EtOAc/hexanes to givethe product as an orange solid (0.676 g, 2.34 mmol, 85%): ¹H NMR (400MHz, CDCl₃) δ 7.21-7.17 (m, 2H), 7.05-7.00 (m, 2H), 4.57 (s, 2H), 3.63(t, J=4.8 Hz, 4H), 2.98 (t, J=5.2 Hz, 4H), 2.31 (s, 3H).

A solution of this product (0.0400 g, 0.139 mmol), thiophenol (0.0610 g,0.554 mmol), and Cs₂CO₃ (0.0903 g, 0.277 mmol) in DMF (0.28 mL) wasstirred at 80° C. for 2 d. The reaction mixture was diluted with brine(10 mL) and extracted with EtOAc (20 mL). The organic layer wasseparated, washed with brine (2×10 mL), dried (Na₂SO₄), and concentratedin vacuo. The crude material was purified by chromatography on SiO₂(1:4, EtOAc/hexanes) the product as a clear colorless oil (0.0257 g,0.0709 mmol, 51%): IR (ATR) 3054, 2918, 2823, 1598, 1581, 1493, 1440,1342, 1324, 1262, 1225, 1153, 1112, 1070, 954, 765, 744, 725, 691 cm⁻¹;¹H NMR (500 MHz, CDCl₃) δ 7.59 (d, J=7.5 Hz, 2H), 7.39-7.30 (m, 3H),7.21-7.14 (m, 2H), 7.02 (t, J=7.5 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 4.33(s, 2H), 3.51 (t, J=4.5 Hz, 4H), 2.92 (t, J=4.5 Hz, 4H), 2.28 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 150.7, 133.4, 132.7, 131.2, 131.1, 129.4,128.1, 126.7, 123.9, 119.4, 54.2, 51.8, 46.8, 17.7; HRMS (+ESI) m/zcalcd for C₁₈H₂₃N₂O₂S₂ ([M+H]⁺) 363.1195, found 363.1190.

2-4(3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-phenylpiperazin-1-yl)ethanone(5a). To a solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)aceticacid 3a (0.0200 g, 0.0994 mmol) in CH₂Cl₂ (1.25 mL) was added1-phenylpiperazine 4a (0.0190 g, 0.119 mmol) and Et₃N (41 μL, 0.298mmol). The reaction mixture was cooled to 0° C., treated with T3P (50wt. % solution in EtOAc, 105 μL, 0.149 mmol), allowed to warm to roomtemperature, stirred for 2 d, diluted with CH₂Cl₂ and washed with satd.aqueous NH₄Cl, satd. aqueous NaHCO₃, brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, liquid load in CH₂Cl₂,EtOAc/hexanes gradient (10-100%), product eluted at 60%) to give 5a(0.0330 g, 0.0955 mmol, 96%, 100% pure by ELSD) as a colorless solid: Mp74-75° C.; IR (ATR) 2856, 2802, 1627, 1599, 1496, 1440, 1416, 1229,1141, 1034, 909, 765, 698 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.26-7.21 (m,1H), 6.89-6.83 (m, 3H), 3.72 (app t, 2H, J=5.2 Hz), 3.56 (s, 2H),3.56-3.54 (m, 2H), 3.18 (s, 2H), 3.15-3.10 (m, 2H), 2.34 (s, 3H), 2.23(s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 165.8, 158.6, 149.8, 128.2,119.6, 115.6, 108.7, 48.5, 48.3, 45.3, 40.7, 31.0, 22.7, 10.0, 9.1; HRMS(ESI) m/z calcd for C₁₈H₂₄N₃O₂S ([M+H]⁺) 346.1584, found: 346.1571.

2-4(3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(o-tolyl)piperazin-1-yl)ethanone(5b). To a solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)aceticacid (3a, 0.0200 g, 0.0994 mmol) in CH₂Cl₂ (1.25 mL) was added1-(o-tolyl)piperazine 4b (0.0210 g, 0.119 mmol) and Et₃N (41 μL, 0.298mmol). The reaction mixture was cooled to 0° C., treated with T3P (50wt. % solution in EtOAc, 105 μL, 0.149 mmol), allowed to warm to roomtemperature, stirred for 2 d, diluted with CH₂Cl₂ and washed with satd.aqueous NH₄Cl, satd. aqueous NaHCO₃, brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, liquid load in CH₂Cl₂,EtOAc/hexanes gradient (10-100%), product eluted at 40%) to give 5b(0.0348 g, 0.0968 mmol, 97%, 100% pure by ELSD) as a colorless solid: Mp89-91° C.; IR (ATR) 2959, 2828, 1631, 1492, 1430, 1261, 1226, 1138,1036, 979, 959, 776, 726 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.18 (dd, 2H,J=9.0, 7.5 Hz), 7.01 (dd, 2H, J=14.1, 9.0 Hz), 3.76 (app t, 2H, J=4.9Hz), 3.63 (s, 2H), 3.59 (app t, 2H, J=4.9 Hz), 3.24 (s, 2H), 2.93 (appt, 2H, J=4.9 Hz), 2.88 (app t, 2H, J=4.9 Hz), 2.43 (s, 3H), 2.32 (s,3H), 2.30 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 165.8, 158.7, 149.6,131.7, 130.2, 125.7, 122.8, 118.1, 108.7, 50.8, 50.6, 46.0, 41.3, 31.1,22.7, 16.7, 10.0, 9.1; HRMS (ESI) m/z calcd for C₁₉H₂₆N₃O₂S ([M+H]⁺)360.1740, found 360.1725.

2-4(3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(m-tolyl)piperazin-1-yl)ethanone(5c). A solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)aceticacid (3a, 0.0200 g, 0.0994 mmol) in CH₂Cl₂ (1.25 mL) was added1-(m-tolyl)piperazine (4c, 21 μL, 0.119 mmol), Et₃N (41 μL, 0.298 mmol).The reaction mixture was cooled to 0° C., treated with T3P (50 wt. %solution in EtOAc, 105 μL, 0.149 mmol), allowed to warm to roomtemperature, stirred for 2 d, diluted with CH₂Cl₂ and washed with satd.aqueous NH₄Cl, satd. aqueous NaHCO₃, brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, liquid load in CH₂Cl₂,EtOAc/hexanes gradient (10-100%), eluted at 60%) to give 5c (0.0343 g,0.954 mmol, 96%, 99.5% pure by ELSD) as a yellow oil: IR (ATR) 2918,2819, 1635, 1600, 1493, 1424, 1244, 1192, 1145, 995, 957, 775, 729, 694cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.17 (app t, 1H, J=7.8 Hz), 6.75-6.72(m, 3H), 3.76 (app t, 2H, J=5.2 Hz), 3.61 (s, 2H), 3.60-3.58 (m, 2H),3.23 (s, 2H), 3.17 (ddd, 4H, J=5.5, 5.2, 5.0 Hz), 2.41 (s, 3H), 2.32 (s,3H), 2.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.5, 165.8, 158.6, 149.8,138.0, 128.1, 120.5, 116.5, 112.8, 108.7, 48.6, 48.5, 45.3, 40.8, 31.0,22.7, 20.7, 10.0, 9.1; HRMS (ESI) m/z calcd for C₁₉H₂₆N₃O₂S ([M+H]⁺)360.1740, found: 360.1725.

2-4(3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(p-tolyl)piperazin-1-yl)ethanone(5d). A solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)aceticacid (3a, 0.0200 g, 0.0994 mmol) in CH₂Cl₂ (1.25 mL) was added1-(p-tolyl)piperazine (4d, 21 μL, 0.119 mmol), Et₃N (41 μL, 0.298 mmol).The reaction mixture was cooled to 0° C., treated with T3P (50 wt. %solution in EtOAc, 105 μL, 0.149 mmol), allowed to warm to roomtemperature, stirred for 2 d, diluted with CH₂Cl₂, washed with satd.aqueous NH₄Cl, satd. aqueous NaHCO₃, and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, liquid load in CH₂Cl₂,EtOAc/hexanes gradient ((10-100%), eluted at 60%) to give 5d (0.0266 g,0.0740 mmol, 74%, 100% pure by ELSD) as a red solid: Mp 83-85° C.; IR(ATR) 2855, 2801, 1627, 1514, 1440, 1416, 1261, 1230, 1142, 1043, 960,815, 724 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.10 (d, 2H, J=8.1 Hz), 6.85(d, 2H, J=8.1 Hz), 3.77 (app t, 2H, J=4.7 Hz), 3.61-3.58 (m, 4H), 3.23(s, 2H), 3.13 (ddd, 4H, J=5.6, 5.5, 4.7 Hz), 2.41 (s, 3H), 2.28, (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ 167.5, 166.8, 159.7, 148.7, 130.3, 129.8,117.0, 109.7, 50.1, 49.9, 46.4, 41.8, 32.1, 23.7, 20.4, 11.0, 10.1; HRMS(ESI) m/z calcd for C₁₉H₂₆N₃O₂S ([M+H]⁺) 360.1740, found 360.1725.

2-(4-(2-(((3,5-Dimethylisoxazol-4-yl)methyl)thio)acetyl)piperazin-1-yl)benzonitrile(MK415-62; 5e). To a solution of([(3,5-dimethylisoxazol-4-yl)methyl]thio)acetic acid (3a, 0.0280 g,0.132 mmol) in CH₂Cl₂ (1.3 mL) was added 2-(piperazin-1-yl)benzonitrile(4e, 0.0253 g, 0.132 mmol) and Et₃N (56 μL, 0.400 mmol). The reactionmixture was cooled to 0° C., treated with T3P (50 wt. % solution inEtOAc, 140 μL 0.200 mmol), allowed to warm to room temperature, stirredfor 20 h, diluted with CH₂Cl₂, washed with satd. aqueous NH₄Cl, satd.aqueous NaHCO₃, and brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The crude residue was purified by chromatography on SiO₂ (95:5,CH₂Cl₂/MeOH) to give 5e (0.0390 g, 0.105 mmol, 80%, 99.9% pure by ELSD)as a yellow solid: Mp 142-143° C.; IR (neat) 2919, 2216, 1637, 1593,1420, 1232 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (dd, 1H, J=7.6, 1.6 Hz),7.51 (ddd, 1H, J=8.4, 7.6, 1.6 Hz), 7.09 (dt, 1H, J=7.6, 0.9 Hz), 7.02(d, 1H, J=8.4 Hz), 3.82 (app t, 2H, J=4.8 Hz), 3.67 (app t, 2H, J=4.8Hz), 3.62 (s, 2H), 3.24 (s, 2H), 3.24-3.21 (m, 2H) 3.15 (app t, 2H,J=5.4 Hz), 2.41 (s, 3H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.6,166.7, 159.6, 154.9, 134.3, 133.9, 122.7, 118.9, 118.0, 109.7, 106.7,51.9, 51.1, 46.6, 41.8, 32.1, 23.7, 11.0, 10.1; HRMS (ESI) m/z calcd forC₁₉H₂₃N₄O₂S ([M+H]⁺) 371.1542, found 371.1536.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(2-fluorophenyl)piperazin-1-yl)ethan-1-one(BRE454-54; 5f). To a solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid (3a, 0.0758 g,0.377 mmol) in CH₂Cl₂ (3.8 mL) was added 1-(2-fluorophenyl)-piperazine(4f, 0.0814 g, 0.452 mmol) and Et₃N (262 μL, 1.88 mmol). The reactionmixture was cooled to 0° C., treated with T3P (50 wt. % solution inEtOAc, 399 μL, 0.565 mmol), allowed to warm to room temperature, stirredfor 20 h, diluted with CH₂Cl₂, and washed with satd. aqueous NH₄Clsolution, satd. aqueous NaHCO₃ solution, and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (3:2, EtOAc/hexanes, base washed with 0.1% Et₃Nprior to use) to give 5f (0.134 g, 0.369 mmol, 98%, 100% pure by ELSD)as a light yellow oil: IR (ATR) 2918, 2827, 1636, 1613, 1500, 1439,1237, 1195, 1147, 1031, 909, 811, 753, 725 cm⁻¹; ¹H NMR (400 MHz, CDCl₃)δ 7.10-6.90 (m, 4H), 3.79 (app t, 2H, J=5.2 Hz), 3.63-3.59 (m, 4H), 3.23(s, 2H), 3.10 (app t, 2H, J=4.8 Hz), 3.05 (app t, 2H, J=5.2 Hz), 2.28(s, 3H), 2.42 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.5, 166.8, 159.7,155.7 (d, J_(C-F)=245.0 Hz), 139.4 (d, J_(C-F)=8.8 Hz), 124.5 (d,J_(C-F)=3.8 Hz), 123.3 (d, J_(C-F)=8.8 Hz), 119.2 (d, J_(C-F)=2.5 Hz),116.3 (d, J_(C-F)=20.0 Hz), 109.7, 50.7 (d, J_(C-F)=2.5 Hz), 50.3 (d,J_(C-F)=2.5 Hz), 46.6, 41.9, 32.1, 23.7, 11.1, 10.2; HRMS (ESI) m/zcalcd for C₁₈H₂₃N₃O₂FS ([M+H]⁺) 364.1490, found 364.1474.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(naphthalen-1-yl)piperazin-1-yl)ethanone(5g). A Schlenk flask was charged under N₂ with piperazine (0.0500 g,0.580 mmol), NaO-t-Bu (0.100 g, 1.06 mmol), (rac)-BINAP (0.0051 g,0.0079 mmol), Pd₂(dba)₃ (0.0050 g, 0.0053 mmol), and degassed toluene (5mL). After addition of 1-bromonaphthalene (75 μL, 0.530 mmol), thereaction mixture was heated at 110° C. for 24 h, cooled to roomtemperature, diluted with CH₂Cl₂, filtered through Celite, andconcentrated in vacuo. The resulting 1-(naphthalen-1-yl)piperazine (4 g)was used without further purification for the next reaction.

To a solution of (((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid(3a, 0.0580 g, 0.272 mmol) in CH₂Cl₂ (4 mL) was added1-(naphthalen-1-yl)piperazine 4 g (0.0750 g, 0.353 mmol) and Et₃N (114μL, 0.815 mmol). The reaction mixture was cooled to 0° C., treated withT3P (50 wt. % solution in EtOAc, 288 μL, 0.408 mmol), allowed to warm toroom temperature, stirred for 20 h, diluted with CH₂Cl₂, and washed withsatd. aqueous NH₄Cl, satd. aqueous NaHCO₃, and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (95:5 CH₂Cl₂/MeOH) to give 5g (0.0700 g, 0.177mmol, 65% 2 steps, 99.9% pure by ELSD) as a yellow oil: IR (neat) 2919,1637, 1435, 1398, 1215, 1192 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d,1H, J=7.5 Hz), 7.85 (d, 1H, J=7.5 Hz), 7.61 (d, 1H, J=8.0 Hz), 7.54-7.49(m, 2H), 7.42 (d, 1H, J=8.0 Hz), 7.08 (d, 1H, J=7.5 Hz), 3.73-3.66 (m,4H), 3.64 (s, 2H), 3.28 (s, 2H), 3.27-2.85 (m, 4H), 2.45 (s, 3H), 2.32(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.6, 166.8, 159.7, 148.7, 134.7,128.7, 128.5, 126.0, 125.7 (2 C), 124.2, 123.0, 115.0, 109.7, 52.9,52.7, 47.0, 42.4, 32.1, 23.7, 11.1, 10.2; HRMS (ESI) m/z calcd forC₂₂H₂₆N₃O₂S ([M+H]⁺) 396.1746, found 396.1740.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(2-methoxyphenyl)piperazin-1-yl)ethanone(5h). To a solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)aceticacid (3a, 0.0200 g, 0.0994 mmol) in CH₂Cl₂ (1.25 mL) was added1-(o-methoxyphenyl)piperazine (4h, 0.0230 g, 0.119 mmol) and Et₃N (41 μL0.298 mmol). The reaction mixture was cooled to 0° C., treated with T3P(50 wt. % solution in EtOAc, 105 μL 0.149 mmol), warmed to roomtemperature, stirred for 2 d, diluted with CH₂Cl₂ and washed with satd.aqueous NH₄Cl, satd. aqueous NaHCO₃, and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, liquid load in CH₂Cl₂,EtOAc/hexanes gradient (10-100%, eluted at 50-70%) to give 5h (0.0195 g,0.0519 mmol, 52%, 100% pure by ELSD) as a colorless solid: Mp 91-93° C.;IR (ATR) 2997, 2926, 2812, 1626, 1500, 1447, 1243, 1223, 1143, 1023,979, 751, 741, 726 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.06-7.01 (m, 1H),6.95-6.87 (m, 3H), 3.87 (s, 3H), 3.80 (app t, 2H, J=5.0 Hz), 3.64-3.62(m, 4H), 3.23 (s, 2H), 3.07 (app t, 2H, J=5.0 Hz), 3.03 (app t, 2H,J=5.0 Hz), 2.41 (s, 3H), 2.28 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.4,166.7, 159.8, 152.2, 140.4, 123.6, 121.0, 118.4, 111.3, 109.7, 55.4,50.7, 50.5, 46.7, 42.0, 32.1, 23.7, 11.0, 10.1; HRMS (ESI) m/z calcd forC₁₉H₂₆N₃O₂₃S ([M+H]⁺) 376.1689, found 376.1673.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)thio)-N-methyl-N-(2-(methyl(o-tolyl)amino)ethyl)acetamide (5i). To a solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid (3a, 0.0608 g,0.302 mmol) in CH₂Cl₂ (3.0 mL) was addedN,N′-dimethyl-N-(o-tolyl)ethane-1,2-diamine (4i, 0.0500 g, 0.275 mmol)and Et₃N (115 μL, 0.825 mmol). The reaction mixture was cooled to 0° C.,treated with T3P (50 wt. % solution in EtOAc, 292 μL, 0.412 mmol),warmed to room temperature, stirred for 20 h, diluted with CH₂Cl₂, andwashed with satd. aqueous NH₄Cl solution, satd. aqueous NaHCO₃ solution,and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by chromatography on SiO₂ (3:2,EtOAc/hexanes, base washed with 0.1% Et₃N prior to use) to give 5i(0.0752 g, 0.207 mmol, 75%, 99.6% pure by ELSD) as a light yellow oil:IR (ATR) 2932, 2795, 1640, 1598, 1493, 1451, 1421, 1393, 1196, 1108,1047, 766, 738 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, room temperature, mixtureof rotamers coalescing in DMSO-d₆ at 357 K) δ 7.20-7.12 (m, 2H),7.07-6.95 (m, 2H), 3.59, 3.58 (2s, 2H), 3.54 (t, 1H, J=6.6 Hz), 3.39 (t,1H, J=6.6 Hz), 3.16-3.08 (m, 3H), 2.97, 2.95 (2s, 4H), 2.71, 2.67 (2s,3H), 2.38 (s, 3H), 2.30 (s, 2H), 2.27, 2.26 (3s, 4H); ¹³C NMR (125 MHz,CDCl₃, room temperature, mixture of rotamers coalescing in DMSO-d₆ at357 K) δ 169.2, 168.8, 166.7 (2 C), 159.7, 151.7, 150.8, 133.8, 132.9,131.4, 131.2, 126.7, 126.5, 124.0, 123.2, 120.2, 119.9, 109.8, 53.9,53.2, 48.4, 46.4, 43.3, 42.3, 36.7, 33.8, 32.4, 31.6, 23.7, 23.4, 18.2,18.0, 11.0 (2 C), 10.1; HRMS (ESI) m/z calcd for C₁₉H₂₈N₃O₂S ([M+H]⁺)362.1897, found 362.1890.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(4-(o-tolyl)-1,4-diazepan-1-yl)ethan-1-one(BRE454-76; 5j). A solution of tert-butyl4-(o-tolyl)-1,4-diazepane-1-carboxylate (29a, 0.0750 g, 0.258 mmol) inTHF (0.3 mL) was cooled to 0° C., treated with 4 M HCl in dioxane (1.6mL) and stirred at 0° C. for 2 h. The reaction mixture was concentratedin vacuo and the yellow solid 4j was precipitated in Et₂O, filtered offfrom the solution, washed with Et₂O, dried under high vacuum, and usedwithout further purification for the next step.

To a solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid(3a, 0.0460 g, 0.229 mmol) in CH₂Cl₂ (2.3 mL) was added4-(o-tolyl)-1,4-diazepane hydrochloride (4j, 0.258 mmol) and Et₃N (159μL, 1.14 mmol). The reaction mixture was cooled to 0° C., treated withT3P (50 wt. % solution in EtOAc, 242 μL, 0.343 mmol), warmed to roomtemperature, stirred for 20 h, diluted with CH₂Cl₂, and washed withsatd. aqueous NH₄Cl solution, satd. aqueous NaHCO₃ solution, and brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude residuewas purified by chromatography on SiO₂ (3:2, EtOAc/hexanes, base washedwith 0.1% Et₃N) to give 5j (0.0854 g, 0.229 mmol, quant. 100% pure byELSD) as a clear colorless oil: IR (ATR) 2945, 2825, 1634, 1598, 1491,1447, 1423, 1215, 1194, 1136, 915, 762, 726 cm⁻¹; ¹H NMR (400 MHz,CDCl₃, room temperature, mixture of rotamers) δ 7.20 (app d, 1H, J=7.6Hz), 7.17 (app t, 1H, J=7.6 Hz), 7.05 (app d, 1H, J=7.6 Hz), 7.01 (appdt, 1H, J=7.2, 2.0 Hz), 3.82-3.78 (m, 2H), 3.71-3.65 (m, 4H), 3.24-3.20(m, 3H), 3.15 (t, 1H, J=5.2 Hz), 3.12-3.07 (m, 2H), 2.46 (app s, 3H),2.32 (2s, 6H), 2.04 (sept, 2H, J=6.0 Hz); ¹³C NMR (125 MHz, CDCl₃, roomtemperature, mixture of rotamers) δ 168.9, 168.8, 166.9, 166.8, 159.8 (2C), 153.4, 153.3, 132.9 (2 C), 131.1 (2 C), 126.7, 126.6, 123.6, 123.4,120.8, 120.7, 109.9, 56.4, 55.8, 55.5, 54.9, 50.1, 47.6, 47.2, 44.9,32.2, 32.0, 29.5, 28.2, 23.7, 18.5 (2 C), 11.1, 10.2 (2 C); HRMS (ESI)m/z calcd for C₂₀H₂₈N₃O₂S ([M+H]⁺) 374.1897, found 374.1883.

1-(2,6-Dimethyl-4-(o-tolyl)piperazin-1-yl)-2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)ethanone(5k). A solution of (((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid(3a, 0.0300 g, 0.142 mmol) in CH₂Cl₂ (2 mL) was treated with3,5-dimethyl-1-(o-tolyl)piperazine (4k, 0.0350 g, 0.170 mmol) and Et₃N(59 μL, 0.425 mmol). The reaction mixture was cooled to 0° C., treatedwith T3P (50 wt. % solution in EtOAc, 150 μL, 0.212 mmol), warmed toroom temperature, stirred for 20 h, diluted with CH₂Cl₂, and washed withsatd. aqueous NH₄Cl, satd. aqueous NaHCO₃, and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (95:5 CH₂Cl₂/MeOH) to give 5k (0.0450 g, 0.116mmol, 82%, 99.8% pure by ELSD) as a light yellow oil: IR (neat) 2975,1629, 1491, 1422, 1327, 1127 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.22-7.19(m, 2H), 7.06-7.02 (m, 2H), 4.68 (brs, 1H), 4.05 (brs, 1H), 3.73-3.70(m, 1H), 3.66-3.61 (m, 1H), 3.30-3.19 (m, 2H), 2.98-2.96 (m, 2H),2.94-2.89 (m, 1H), 2.81-2.78 (m, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 2.31(s, 3H), 1.55 (d, 3H, J=6.0 Hz), 1.48 (d, 3H, J=6.0 Hz); ¹³C NMR (125MHz, CDCl₃) δ 168.2, 166.7, 151.2, 133.3, 131.2, 126.8, 124.1, 119.6,109.8, 57.0, 56.8, 49.8, 45.8, 32.0, 23.6, 21.6, 20.3, 18.2, 11.0, 10.1;HRMS (ESI) m/z calcd for C₂₁H₃₀N₃O₂S ([M+H]⁺) 388.2059, found 388.2053.

1-(3,5-Dimethyl-4-phenylpiperazin-1-yl)-2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)ethan-1-one(5l). A solution of tert-butyl3,5-dimethyl-4-phenylpiperazine-1-carboxylate (29b, 0.0330 g, 0.114mmol) in THF (0.1 mL) at 0° C. was treated with 4 M HCl in dioxane (0.70mL) and stirred at 0° C. for 1.5 h and at room temperature for 1.5 h.The yellow solid was filtered off, washed with Et₂O, dried under highvacuum and the resulting crude 4l was directly used for the next step.

To a solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid3a (0.0229 g, 0.114 mmol) in CH₂Cl₂ (1.1 mL) was added2,6-dimethyl-1-phenylpiperazine hydrochloride (4l, 0.0258 g, 0.114 mmol)and Et₃N (79 μL, 0.569 mmol). The reaction mixture was cooled to 0° C.,treated with T3P (50 wt. % solution in EtOAc, 121 μL, 0.171 mmol),warmed to room temperature, stirred for 20 h, diluted with CH₂Cl₂, andwashed with satd. aqueous NH₄Cl solution, satd. aqueous NaHCO₃ solution,and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by chromatography on SiO₂ (1:1,acetone/hexanes, base washed with 0.1% Et₃N prior to use) to give 5l(0.0322 g, 0.0862 mmol, 76%, 100% pure by ELSD) as a colorless oil: IR(ATR) 2967, 2931, 1639, 1597, 1493, 1449, 1377, 1319, 1272, 1238, 1151,1091, 886, 771, 731, 703 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.31 (t, 2H,J=7.6 Hz), 7.18 (t, 1H, J=7.2 Hz), 7.10 (d, 2H, J=7.6 Hz), 4.42 (ddd,1H, J=12.8,4.0,2.4 Hz), 3.70-3.60 (m, 3H), 3.29-3.18 (m, 2H), 3.10-2.93(m, 3H), 2.67 (dd, 1H, J=13.2, 10.4 Hz), 2.43 (s, 3H), 2.30 (s, 3H),0.77 (d, 3H, J=6.4 Hz), 0.76 (d, 3H, J=5.6 Hz); ¹³C NMR (100 MHz, CDCl₃)δ 167.1, 166.8, 159.7, 148.5, 128.9, 126.4, 125.6, 109.8, 56.0, 55.6,53.4, 48.7, 31.9, 23.7, 18.2, 18.2, 11.1, 10.2; HRMS (ESI) m/z calcd forC₂₀H₂₈N₃O₂S ([M+H]⁺) 374.1897, found 374.1887.

1-(3,5-Dimethyl-4-(m-tolyl)piperazin-1-yl)-2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)ethan-1-one(5m). A solution of tert-butyl3,5-dimethyl-4-(m-tolyl)piperazine-1-carboxylate (29c, 0.0400 g, 0.131mmol) in THF (0.1 mL) at 0° C. was treated with 4 M HCl in dioxane (0.80mL), and stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. Ayellow precipitate formed and the solid was filtered off, washed withEt₂O, and dried under high vacuum and the resulting crude 4m was useddirectly for the next step.

To a solution of 2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid(3a, 0.0264 g, 0.131 mmol) in CH₂Cl₂ (1.3 mL) was added2,6-dimethyl-1-(m-tolyl)piperazine hydrochloride (4m, 0.0316 g, 0.131mmol) and Et₃N (91 μL, 0.656 mmol). The reaction mixture was cooled to0° C., treated with T3P (50 wt. % solution in EtOAc, 139 μL, 0.197mmol), warmed to room temperature, stirred for 20 h, diluted withCH₂Cl₂, washed with satd. aqueous NH₄Cl solution, satd. aqueous NaHCO₃solution, and brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The crude residue was purified by chromatography on SiO₂ (3:2,EtOAc/hexanes, base washed with 0.1% Et₃N prior to use) to give 5m(0.0400 g, 0.103 mmol, 79%, 100% pure by ELSD) as a clear colorless oil:IR (ATR) 2966, 2929, 1637, 1602, 1451, 1376, 1319, 1271, 1194, 1149,1108, 1088, 911, 889, 788, 730, 709 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.18(t, 1H, J=7.6 Hz), 6.97 (d, 1H, J=7.6 Hz), 6.90-6.88 (m, 2H), 4.41 (appd, 1H, J=12.8 Hz), 3.64 (brs, 3H), 3.27-3.19 (m, 2H), 3.15-2.91 (m, 3H),2.67 (t, 1H, J=9.2 Hz), 2.43 (s, 3H), 2.32 (s, 3H), 2.30, (s, 3H), 0.77(br app s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 167.1, 166.8, 159.7, 148.4,138.7, 128.7, 127.1, 126.4, 123.4, 109.8, 56.0, 55.6, 53.4, 48.7, 32.0,23.7, 21.4, 18.3, 18.2, 11.1, 10.2; HRMS (ESI) m/z calcd for C₂₁H₃₀N₃O₂S([M+H]⁺) 388.2053, found 388.2046.

3,5-Dimethyl-4-(((2-(4-(o-tolyl)piperazin-1-yl)ethyl)thio)methyl)isoxazole(6). A solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(o-tolyl)piperazin-1-yl)ethanone(5b, 0.0387 g, 0.108 mmol) in THF (1 mL) at 0° C. was treated withLiAlH₄ (1 M solution in Et₂O, 120 μL, 0.118 mmol), stirred at 0° C. for1 h, and then quenched with Rochelle's salt (NaKC₄H₄O₆, satd. aqueoussolution, 1 mL). The mixture was stirred for an additional 1 h at 0° C.,diluted with EtOAc, extracted with EtOAc (2×15 mL), dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 4 g column, liquid load in CH₂Cl₂, 0-20%MeOH/CH₂Cl₂, product eluted at 5% MeOH) to give a colorless oil. Thisoil was further purified by chromatography on SiO₂ (CH₂Cl₂ to 5:95,MeOH/CH₂Cl₂) on a pipette column to give 6 (0.0155 g, 0.0449 mmol, 42%,100% pure by ELSD) as a colorless oil: IR (neat) 3393, 2925, 2814, 1637,1599, 1493, 1448, 1424, 1372, 1227, 1195, 1130, 1041, 1006, 931, 763,723 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.16 (app t, 2H, J=7.4 Hz),7.03-6.95 (m, 2H), 3.75 (t, 1H, J=5.7 Hz), 3.50 (s, 2H), 2.93 (app t,4H, J=4.5 Hz), 2.63 (brs, 8H), 2.38 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H);¹³C NMR (75 MHz, CDCl₃) δ 165.9, 159.6, 151.4, 132.6, 131.0, 126.6,123.2, 119.0, 110.5, 77.2, 58.1, 53.6, 51.6, 29.1, 24.0, 23.5, 17.8,11.1, 10.2; HRMS (ESI) m/z calcd for C₁₉H₂₈ON₃S ([M+H]⁺) 346.1948, found346.1946.

2-(Benzylthio)-1-(4-(o-tolyl)piperazin-1-yl)ethanone (7). A solution of2-(benzylthio)acetic acid 3b (0.0440 g, 0.241 mmol) in CH₂Cl₂ (3.05 mL)was treated with 1-(o-tolyl)piperazine 4b (0.0521 g, 0.290 mmol) andEt₃N (101 μL, 0.724 mmol). The reaction mixture was cooled to 0° C.,treated with T3P (50 wt. % solution in EtOAc, 256 μL, 0.362 mmol),warmed to room temperature and stirred for 2 d. The solution was dilutedwith CH₂Cl₂ and washed with satd. aqueous NH₄Cl, satd. aqueous NaHCO₃,and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by chromatography on SiO₂ (ISCO, 12 g column,liquid load in CH₂Cl₂, EtOAc/hexanes gradient (10-100%)) to give 7(0.0635 g, 0.187 mmol, 77%, 100% pure by ELSD) as a yellow oil: IR (ATR)2917, 1815, 1634, 1598, 1492, 1437, 1223, 1150, 1031, 975, 761, 700cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.23 (m, 7H), 7.06-7.01 (m, 2H),3.89 (s, 2H), 3.79 (app t, 2H, J=4.9 Hz), 3.59 (app t, 2H, J=4.9 Hz),3.30 (s, 2H), 2.95-2.90 (m, 4H), 2.37 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ167.7, 150.9, 137.7, 132.8, 131.2, 129.3, 128.5, 127.2, 126.7, 123.8,119.3, 51.9, 51.7, 46.9, 42.4, 36.3, 32.4, 17.8; HRMS (ESI) m/z calcdfor C₂₀H₂₅N₂OS ([M+H]⁺) 341.1682, found: 341.1674.

4-Phenyl-1-(4-(o-tolyl)piperazin-1-yl)butan-1-one (8). To a solution ofphenyl butanoic acid (3c, 0.0500 g, 0.305 mmol) in CH₂Cl₂ (3.05 mL) wasadded 1-(o-tolyl)piperazine (4b, 0.0657 g, 0.365 mmol) and Et₃N (85 μL,0.609 mmol). The reaction mixture was cooled to 0° C., treated with T3P(50 wt. % solution in EtOAc, 322 μL, 0.457 mmol), warmed to roomtemperature, stirred overnight, diluted with CH₂Cl₂ and washed withsatd. aqueous NH₄Cl, satd. aqueous NaHCO₃, and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, liquid load in CH₂Cl₂,EtOAc/hexanes gradient (10-100%), eluted at 30%) to give 8 (0.0863 g,0.268 mmol, 88%, 100% pure by ELSD) as a colorless oil: IR (ATR) 3024,2917, 2813, 1641, 1492, 1432, 1223, 1150, 1025, 761, 722 cm⁻¹; ¹H NMR(300 MHz, CDCl₃) δ 7.36-7.31 (m, 2H), 7.27-7.18 (m, 5H), 7.07-6.99 (m,2H), 3.80 (app t, 2H, J=4.8 Hz), 3.55 (app t, 2H, J=4.8 Hz), 2.88 (appt, 4H, J=4.8 Hz), 2.75 (t, 2H, J=7.5 Hz), 2.41 (t, 2H, J=7.5 Hz), 2.36(s, 3H), 2.06 (ddd, 2H, J=7.9, 7.7, 7.3 Hz); ¹³C NMR (75 MHz, CDCl₃) δ171.2, 150.8, 141.6, 132.6, 131.0, 128.4, 128.3, 126.6, 125.8, 123.6,119.0, 51.9, 51.6, 45.9, 41.9, 35.2, 32.3, 26.6, 17.7; HRMS (ESI) m/zcalcd for C₂₁H₂₇N₂O ([M+H]⁺) 323.2118, found: 323.2110.

2-(Phenylthio)-1-(4-(o-tolyl)piperazin-1-yl)ethan-1-one (9). To asolution of 2-(phenylthio)acetic acid (3d, 0.0500 g, 0.297 mmol) inCH₂Cl₂ (3.0 mL) was added 1-(o-tolyl)piperazine (4b, 0.0642 g, 0.357mmol) and Et₃N (83 μL, 0.594 mmol). The mixture was cooled to 0° C.,treated with T3P (50 wt. % solution in EtOAc, 315 μL, 0.446 mmol),warmed to room temperature, stirred for 3 d, diluted with CH₂Cl₂ andwashed with satd. aqueous NH₄Cl, satd. aqueous NaHCO₃, and brine. Theorganic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude residue was purified by chromatography on SiO₂ (ISCO, 4 gcolumn, liquid load in CH₂Cl₂, EtOAc/hexanes gradient (0-30%), eluted at20-30%) to give 9 (0.0746 g, 0.229 mmol, 77%, 100% pure by ELSD) as aclear colorless oil: IR (ATR) 3057, 2947, 2911, 2856, 2815, 1639, 1598,1492, 1482, 1382, 1275, 1223, 1203, 1149, 1115, 1032, 974, 950, 909,762, 738, 723, 690 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.48 (dd, 2H, J=7.6,1.2 Hz), 7.34 (app t, 2H, J=7.6 Hz), 7.26-7.17 (m, 3H), 7.02 (app t, 1H,J=7.6 Hz), 6.98 (app d, 1H, J=7.6 Hz), 3.81 (s, 2H), 3.76 (app t, 2H,J=4.8 Hz), 3.63 (app t, 2H, J=4.8 Hz), 2.91 (app t, 2H, J=4.8 Hz), 2.86(t, 2H, J=4.8 Hz), 2.33 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.1,150.7, 134.9, 132.7, 131.2, 130.3, 129.1, 127.0, 126.7, 123.8, 119.2,51.9, 51.6, 47.0, 42.5, 36.7, 17.8; HRMS (ESI) m/z calcd for C₁₉H₂₃N₂OS([M+H]⁺) 327.1526, found 327.1514.

3-Phenyl-1-(4-(o-tolyl)piperazin-1-yl)prop-2-yn-1-one (10). To asolution of phenyl propiolic acid (3e, 0.200 g, 1.37 mmol) in CH₂Cl₂ (12mL) was added 1-(o-tolyl)piperazine (4b, 0.290 g, 1.64 mmol) and Et₃N(570 μL, 4.11 mmol). The reaction mixture was cooled to 0° C., treatedwith T3P (50 wt. % solution in EtOAc, 1.45 mL, 2.05 mmol), warmed toroom temperature, stirred for 3 d, diluted with CH₂Cl₂ (30 mL), andwashed with satd. aqueous NH₄Cl (5 mL), satd. aqueous NaHCO₃ (5 mL), andbrine (5 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by chromatography on SiO₂ (ISCO, 24 g column,liquid load in CH₂Cl₂, EtOAc/hexanes gradient (10-100%), product elutedat 40% EtOAc/hexanes) to give 10 (0.401 g, 1.32 mmol, 96%, >99.9% pureby ELSD) as a colorless solid: Mp 127-129° C.; IR (neat) 3037, 2907,2857, 2206, 1616, 1491, 1424, 1279, 1226, 1207, 1035, 923, 758, 726, 686cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.56 (m, 2H), 7.43-7.34 (m, 3H),7.22-7.16 (m, 2H), 7.05-6.99 (m, 2H), 3.99 (app t, 2H, J=5.0 Hz), 3.85(app t, 2H, J=5.0 Hz), 2.99 (app t, 2H, J=5.0 Hz), 2.92 (app t, 2H,J=5.0 Hz), 2.35 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 153.2, 150.8, 132.8,132.4, 131.2, 130.1, 128.6, 126.8, 123.9, 120.5, 119.3, 90.9, 81.2,52.2, 51.5, 47.7, 42.1, 17.8; HRMS (ESI) m/z calcd for C₂₀H₂₁ON₂([M+H]⁺) 305.1648, found 305.1643.

(E)-3-Phenyl-1-(4-(o-tolyl)piperazin-1-yl)prop-2-en-1-one (11). Asolution of trans-cinnamic acid (3f, 0.0400 g, 0.270 mmol) in CH₂Cl₂(2.5 mL) was treated with 1-(o-tolyl)piperazine (4b, 0.0570 g, 0.320mmol), Et₃N (113 μL, 0.810 mmol). The reaction mixture was cooled to 0°C., treated with T3P (50 wt. % solution in EtOAc, 290 μL, 0.405 mmol),warmed to room temperature, stirred for 3 d, diluted with CH₂Cl₂ (10mL), and washed with satd. aqueous NH₄Cl (2 mL), satd. aqueous NaHCO₃ (2mL), and brine (2 mL), dried (Na₂SO₄), filtered, and concentrated invacuo. The crude residue was purified by chromatography on SiO₂ (ISCO,12 g column, liquid load in CH₂Cl₂, EtOAc/hexanes gradient (10-100%),product eluted at 35%, EtOAc/hexanes) to give 11 (0.0520 g, 0.168 mmol,62%, >99% purity by ELSD) as a yellow solid: Mp 110-111° C.; IR (neat)3045, 2920, 2840, 1643, 1595, 1423, 1327, 1225, 1152, 986, 765, 710, 682cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, 1H, J=11.4 Hz), 7.55 (dd, 2H,J=6.8, 1.4 Hz), 7.41-7.36 (m, 3H), 7.20 (dd, 2H, J=14.6, 7.4 Hz), 7.02(ddd, 2H, J=14.6, 7.4, 0.6 Hz), 6.95 (d, 1H, J=15.6 Hz), 3.90 (brs, 2H),3.81 (brs, 2H), 2.96 (brs, 4H), 2.36 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ165.5, 150.8, 142.8, 135.2, 132.7, 131.1, 129.6, 128.8, 127.7, 126.6,123.7, 119.2, 117.1, 52.1, 51.6, 46.4, 42.6, 17.8; HRMS (ESI) m/z calcdfor C₂₀H₂₃ON₂ ([M+H]⁺) 307.1805, found 307.1796.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)sulfinyl)-1-(4-(o-tolyl)piperazin-1-yl)ethan-1-one(12). To a solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(o-tolyl)piperazin-1-yl)ethanone(5b, 0.0500 g, 0.139 mmol) in MeOH (0.30 mL) at 0° C. was added dropwisea solution of sodium metaperiodate (0.0301 g, 0.139 mmol) in water (0.14mL). The resulting heterogeneous mixture was allowed to warm to roomtemperature and stirred for 15 h. The reaction mixture was filteredthrough a plug of Celite (MeOH), concentrated, dissolved in CH₂Cl₂,dried (MgSO₄), filtered and concentrated in vacuo. The crude residue waspurified by chromatography on SiO₂ (100% EtOAc) to give 12 (0.0356 g,0.0948 mmol, 68%, 100% pure by ELSD) as a colorless foam: IR (ATR) 2917,2818, 1631, 1599, 1493, 1441, 1384, 1275, 1224, 1195, 1151, 1053, 1028,911, 764, 727 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.15 (m, 2H), 7.02(app t, 1H, J=7.2 Hz), 6.97 (app d, 1H, J=8.0 Hz), 4.18 (d, 1H, J=14.0Hz), 3.90-3.84 (m, 5H), 3.64 (app t, 2H, J=4.4 Hz), 2.95 (app t, 2H,J=4.4 Hz), 2.85 (brs, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 169.2, 162.9, 159.9, 150.4, 132.7, 131.2, 126.7,124.0, 119.2, 104.5, 53.7, 52.0, 51.5, 47.0, 46.8, 42.5, 17.7, 11.6,10.3; HRMS (ESI) m/z calcd for C₁₉H₂₆N₃O₃S ([M+H]⁺) 376.1689, found376.1684.

2-(((3,5-Dimethylisoxazol-4-yl)methyl)sulfonyl)-1-(4-(o-tolyl)piperazin-1-yl)ethan-1-one(13). A solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(4-(o-tolyl)piperazin-1-yl)ethanone(5b, 0.0429 g, 0.117 mmol) in CH₂Cl₂ (0.65 mL) was treated with3-chloroperoxybenzoic acid (70 wt. %, 0.0576 g, 0.234 mmol) in 2portions. The reaction mixture was stirred at room temperature for 15 h,quenched with 10% aqueous sodium metabisulfite solution (2 mL), dilutedwith aqueous 1 M NaOH (10 mL) and extracted with CH₂Cl₂ (2×15 mL). Thecombined organic layers were washed with 1 M NaOH (10 mL), dried(MgSO₄), filtered, and concentrated in vacuo. The crude residue waspurified by chromatography on SiO₂ (70-100% EtOAc/hexanes) to give 13(0.0203 g, 0.0519 mmol, 44%, 100% pure by ELSD) as a colorless foam: IR(ATR) 2919, 2819, 1641, 1599, 1493, 1445, 1318, 1225, 1150, 1126, 1030,911, 765, 728 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 2H),7.05-6.98 (m, 2H), 4.36 (s, 2H), 4.09 (s, 2H), 3.85 (app brs, 2H), 3.72(brt, 2H, J=4.0 Hz), 3.00 (brt, 2H, J=4.0 Hz), 2.93 (brt, 2H, J=4.4 Hz),2.50 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ170.1, 160.7, 160.3, 150.3, 132.7, 131.2, 126.7, 124.0, 119.2, 101.8,54.9, 51.7, 51.4, 48.3, 47.8, 43.0, 17.8, 11.5, 10.2; HRMS (ESI) m/zcalcd for C₁₉H₂₆N₃O₄S ([M+H]⁺) 392.1639, found 392.1633.

(Z)-3-Phenyl-1-(4-(o-tolyl)piperazin-1-yl)prop-2-en-1-one (14). To asolution of 3-phenyl-1-(4-(o-tolyl)piperazin-1-yl)prop-2-yn-1-one (10,0.103 g, 0.337 mmol) in MeOH (2 mL) and EtOAc (1 mL) was added Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.120 g) and quinoline (15 μL,0.130 mmol). The reaction mixture was purged and backfilled with H₂(balloon, 2×), allowed to stir for 45 min, filtered through SiO₂, andconcentrated in vacuo. The crude residue was purified by chromatographyon SiO₂ (ISCO, modified dry load in CH₂Cl₂, 0-90% EtOAc/hexanesgradient, product eluted at 25% EtOAc/hexanes) to give 14 (0.104 g,0.339 mmol, quant., 99.6% purity by ELSD) as a yellow oil: IR (neat)3022, 2914, 2815, 1513, 1597, 1493, 1434, 1364, 1223, 1149, 1115, 1034,973, 913, 855, 762, 722, 698 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.30(m, 5H), 7.17-7.11 (m, 2H), 6.98 (t, 1H, J=7.1 Hz), 6.81 (d, 1H, J=7.8Hz), 6.71 (d, 1H, J=12.6 Hz), 6.07 (d, 1H, J=12.6 Hz), 3.81 (app brt,2H, J=4.8 Hz), 3.48 (app t, 2H, J=4.8 Hz), 2.81 (app t, 2H, J=4.8 Hz),2.44 (app t, 2H, J=4.8 Hz), 2.25 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ167.6, 150.9, 135.6, 133.5, 132.7, 131.1, 128.7, 128.6, 128.5, 126.6,123.7, 123.2, 119.1, 51.5, 51.3, 46.8, 41.7, 17.7; HRMS (ESI) m/z calcdfor C₂₀H₂₃ON₂ ([M+H]⁺) 307.1805, found 307.1800.

(2-Phenylcyclopropyl)(4-(o-tolyl)piperazin-1-yl)methanone (15). Asolution of anhydrous CrCl₂ (0.0486 g, 0.392 mmol) in THF (0.6 mL) atroom temperature under N₂ was treated with a solution of(Z)-3-phenyl-1-(4-(o-tolyl)piperazin-1-yl)prop-2-en-1-one (14, 0.0200 g,0.0653 mmol) in THF (0.5 mL) and CH₂ICl (20 μl, 0.261 mmol). Thereaction mixture was stirred for 18 h at reflux, quenched by addition of1 M aqueous HCl (6 mL) and extracted with EtOAc. The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by chromatography on SiO₂ (4:1,EtOAc/hexanes) to give 15 (0.0120 g, 0.0375 mmol, 57%, 100% pure byELSD) as a brown oil: IR (neat) 2920, 1638, 1491, 1457, 1340, 1223, 1028cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.27 (m, 2H), 7.22-7.11 (m, 5H),6.98 (dt, 1H, J=7.2, 1.2 Hz), 6.72 (dd, 1H, J=7.9, 0.8 Hz), 3.93-3.90(m, 1H), 3.77-3.73 (m, 1H), 3.60-3.53 (m, 1H), 3.30-3.22 (m, 1H),2.75-2.72 (m, 2H), 2.50-2.41 (m, 1H), 2.26 (s, 3H), 2.24-2.16 (m, 1H),2.10-2.00 (m, 1H), 1.87 (dd, 1H, J=12.4, 5.8 Hz), 1.40-1.33 (m, 1H),0.92-0.80 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 150.9, 137.6,132.7, 131.0, 128.2, 127.4, 126.5, 126.4, 123.6, 119.2, 51.9, 51.6,45.7, 42.3, 24.4, 24.1, 17.7, 10.6□HRMS (ESI) m/z calcd for C₂₁H₂₅ON₂([M+H]⁺) 321.1967, found 321.1961.

((1SR,2SR)-2-Phenylcyclopropyl)(4-(o-tolyl)piperazin-1-yl)methanone(16). To a solution of trans-2-phenylcyclopropanecarboxylic acid (3g,0.0400 g, 0.247 mmol) in CH₂Cl₂ (2.5 mL) was treated with1-(o-tolyl)piperazine (4b, 0.0540 g, 0.296 mmol), Et₃N (100 μL 0.740mmol). The reaction mixture was cooled to 0° C., treated with T3P (50wt. % solution in EtOAc, 260 μL, 0.370 mmol, 1.5 equiv), warmed to roomtemperature, stirred for 3 d, diluted with EtOAc (10 mL), and washedwith satd. aqueous NH₄Cl (2 mL), satd. aqueous NaHCO₃ (2 mL), and brine(2 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The cruderesidue was purified by chromatography on SiO₂ (ISCO, 12 g column,liquid load in CH₂Cl₂, EtOAc/hexanes gradient (10-90%), product elutedat 20%) to give 16 (0.0676 g, 0.211 mmol, 86%, >99.9% pure by ELSD) as ayellow oil: IR (neat) 3026, 2912, 2814, 1631, 1600, 1493, 1440, 1381,1223, 1150, 1033, 919, 910, 760, 723, 696 cm⁻¹; ¹H NMR (300 MHz, CDCl₃)δ 7.32-7.26 (m, 2H), 7.23-7.12 (m, 5H), 7.01 (dd, 2H, J=11.1, 7.5 Hz),3.79 (brs, 4H), 2.90 (brs, 4H), 2.52 (brpent, 1H, J=4.6 Hz), 2.33 (s,3H), 2.02 (pent, 1H, J=4.6 Hz), 1.71 (pent, 1H, J=4.6 Hz), 1.34-1.26 (m,2H); ¹³C NMR (100 MHz, CDCl₃) δ 170.6, 150.9, 141.0, 132.7, 131.2,128.6, 126.7, 126.3, 126.1, 123.8, 119.2, 52.2, 51.7, 46.2, 25.6, 23.3,17.9, 16.2; HRMS (ESI) m/z calcd for C₂₁H₂₅ON₂ ([M+H]⁺) 321.1961, found321.1957.

2-Chloro-1-(4-(o-tolyl)piperazin-1-yl)ethanone (17a) (Glennon et al., J.Med. Chem. 1986, 29, 2375-2380; Jorand-Lebrun et al., J. Med. Chem.1997, 40, 3974-3978.). To a solution of chloroacetyl chloride (0.698 g,6.05 mmol) and potassium carbonate (1.14 g, 8.25 mmol) in THF (7.0 mL)was added 1-(o-tolyl)piperazine (4b, 1.00 g, 5.50 mmol) in THF (12.6 mL)at 0° C. The reaction mixture was gradually warmed to room temperature,stirred for 16 h, diluted with water, and extracted with EtOAc (3×20mL). The combined organic extracts were washed sequentially with satd.aqueous NaHCO₃, 0.1 M aqueous HCl, and brine, dried (Na₂SO₄), filteredand concentrated in vacuo. The crude solid was filtered through a plugof SiO₂ (3:7, EtOAc/hexanes v/v 1% Et₃N) and washed thoroughly withEtOAc/hexanes (3:7) to give 17a (1.37 g, 5.42 mmol, 99%) as an off whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.16 (m, 2H), 7.05-6.99 (m, 2H),4.12 (s, 2H), 3.78 (app t, 2H, J=4.8 Hz), 3.67 (app t, 2H, J=4.8 Hz),2.97 (app t, 2H, J=4.8 Hz), 2.91 (app t, 2H, J=4.8 Hz), 2.33 (s, 3H).

1-((Chloromethyl)sulfonyl)-4-(o-tolyl)piperazine (17b) (Zhou et al., J.Org. Lett. 2008, 10, 2517-2520.). To a solution of 1-(o-tolyl)piperazine(4b, 0.500 g, 2.75 mmol) in CH₂Cl₂ (9.8 mL) and Et₃N (0.390 mL, 2.75mmol) at 0° C. was added chloromethanesulfonyl chloride (0.460 g, 3.03mmol). The reaction mixture was stirred at 0° C., gradually warmed toroom temperature quenched after 14 h with satd. aqueous NH₄Cl solution(3 mL), and extracted with EtOAc (3×20 mL). The combined organicextracts were washed water (2×10 mL) and brine (10 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude solid was filtered througha plug of SiO₂ (3:7, EtOAc/hexanes containing 1% Et₃N) and washedthoroughly with EtOAc/hexanes (3:7). The combined filtrates wereconcentrated in vacuo to give 17b (0.676 g, 2.34 mmol, 85%) as an orangesolid: ¹H NMR (300 MHz, CDCl₃) δ 7.19 (t, 2H, J=8.1 Hz), 7.03 (t, 2H,J=8.1 Hz), 4.56 (s, 2H), 3.63 (app t, 4H, J=5.0 Hz), 2.99 (app t, 4H,J=5.0 Hz), 2.32 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 150.6, 132.7, 131.2,126.8, 124.1, 119.4, 54.5, 51.9, 47.1, 17.7.

2-((3,5-Dimethylisoxazol-4-yl)methoxy)-1-(4-(o-tolyl)piperazin-1-yl)ethan-1-one(18a). A solution of (3,5-dimethylisoxazol-4-yl)methanol (27, 0.0302 g,0.237 mmol) in THF (0.48 mL) was cooled to 0° C. and NaH (60% dispersionin mineral oil, 0.0190 g, 0.475 mmol) was added. The reaction mixturewas stirred at 0° C. for 30 min, treated with2-chloro-1-(4-(o-tolyl)piperazin-1-yl)ethanone (17a, 0.0600 g, 0.237mmol), warmed to room temperature, stirred for 20 h, quenched with brine(1 mL), diluted with EtOAc (15 mL) and brine (5 mL), and extracted withEtOAc (2×15 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The crude residue was purified by chromatographyon SiO₂ (3:2, EtOAc/hexanes) to give 18a (0.0735 g, 0.214 mmol, 90%,100% pure by ELSD) as a light yellow oil: IR (ATR) 2918, 2817, 1645,1599, 1493, 1443, 1369, 1273, 1225, 1116, 1030, 977, 764, 725 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 2H), 7.02 (dt, 1H, J=7.6, 1.2 Hz),6.97 (app d, 1H, J=8.0 Hz), 4.41 (s, 2H), 4.17 (s, 2H), 3.77 (brs, 2H),3.59 (app t, 2H, J=4.8 Hz), 2.89 (app t, 4H, J=3.6 Hz), 2.41 (s, 3H),2.32 (s, 3H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 167.8, 167.5,159.8, 150.7, 132.7, 131.2, 126.7, 123.9, 119.2, 110.5, 68.7, 61.7,52.1, 51.7, 45.6, 42.3, 17.8, 11.1, 10.1; HRMS (ESI) m/z calcd forC₁₉H₂₆N₃O₃ ([M+H]⁺) 344.1969, found 344.1960.

2-(Benzyl(methyl)amino)-1-(4-(o-tolyl)piperazin-1-yl)ethanone (18b). Asolution of 2-chloro-1-(4-(o-tolyl)piperazin-1-yl)ethanone (17a, 0.0534g, 0.211 mmol), in CH₃CN (4 mL) was treated with N-methylbenzylamine (23μL, 0.176 mmol) and K₂CO₃ (0.730 g, 0.528 mmol). The reaction mixturewas heated at reflux for 5 h, cooled to room temperature, filtered, andconcentrated in vacuo. The crude residue was purified by chromatographyon SiO₂ (2:3, EtOAc/hexanes) to give 18b (0.0590 g, 0.175 mmol,99%, >95% pure by LCMS) as a light yellow oil: IR (neat) 2933, 2816,1640, 1450, 1491, 1222 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.33 (m,4H), 7.31-7.27 (m, 1H), 7.23-7.19 (m, 2H), 7.04 (t, 1H, J=7.5 Hz), 7.01(d, 1H, J=8.0 Hz), 3.77 (brs, 2H), 3.71-3.69 (m, 2H), 3.61 (s, 2H), 3.27(s, 2H), 2.91-2.87 (m, 4H), 2.35 (s, 3H) 2.34 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 150.9, 138.1, 132.6, 131.1, 129.1, 128.2, 127.2, 126.6, 123.6,119.1, 62.0, 60.3, 52.1, 51.7, 46.1, 42.4, 42.2, 17.8; HRMS (ESI) m/zcalcd for C₂₁H₂₈N₃O ([M+H]⁺) 338.2238, found 338.2211.

3,5-Dimethyl-4-(((((4-(o-tolyl)piperazin-1-yl)sulfonyl)methyl)thio)methyl)isoxazole(18c). A suspension of NaH (60% dispersion in mineral oil, 0.0200 g,0.499 mmol) in THF (0.6 mL) was treated under an atmosphere of N₂ at 0°C. with a solution of (3,5-dimethylisoxazol-4-yl)methanethiol (25,0.0536 g, 0.374 mmol) in THF (0.4 mL). The reaction mixture was stirredfor 10 min, treated with1-((chloromethyl)sulfonyl)-4-(o-tolyl)piperazine (17b, 0.0360 g, 0.125mmol), stirred for 2 d at room temperature, quenched (water) andextracted (EtOAc). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was purified bychromatography on SiO₂ (1:4, EtOAc/hexanes) to give crude 18c that wasfurther purified by preparative TLC (2:3, Et₂O/hexanes) to give 18c (2.0mg, 0.00506 mmol, 4%, 100% pure by ELSD) as a colorless oil: IR (neat)2924, 1636, 1450, 1420, 1320, 1152 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.20(t, 2H, J=7.7 Hz), 7.06-7.00 (m, 2H), 3.87 (s, 2H), 3.76 (s, 2H), 3.58(app t, 4H, J=4.8 Hz), 2.99 (app t, 4H, J=4.8 Hz), 2.44 (s, 3H), 2.32(s, 3H), 2.31 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.5, 159.7, 150.6,132.7, 131.2, 126.8, 124.0, 119.4, 108.7, 51.8, 48.6, 47.0, 24.1, 17.8,11.1, 10.2; HRMS (ESI) m/z calcd for C₁₈H₂₆O₃N₃S₂ ([M+H]⁺) 396.1416,found 396.1410.

N-((((3,5-Dimethylisoxazol-4-yl)methyl)thio)methyl)-4-(o-tolyl)piperazine-1-carboxamide(20a). To a solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid (3a, 0.0500 g,0.248 mmol) in toluene (4.0 mL) was added DPPA (57 μL, 0.261 mmol) andEt₃N (37 μL, 0.261 mmol). The reaction mixture was heated at 110° C. for60 min, cooled and washed with satd. aqueous NaHCO₃, dried (MgSO₄),filtered and concentrated to give the isocyanate 19 as a pink oil thatwas used without further purification.

A solution of 1-(o-tolyl)piperazine (4b, 0.460 g, 0.261 mmol) and Et₃N(37 μL, 0.261 mmol) in CH₂Cl₂ (0.5 mL) was cooled to 0° C. and treatedwith a solution of the isocyanate 19 in CH₂Cl₂ (0.5 mL). The reactionmixture was stirred overnight at room temperature, then diluted withEtOAc and satd. aqueous NH₄Cl. The organic layer was washed with satd.aqueous NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by chromatography on SiO₂ (ISCO, 4 gcolumn, gradient hexanes to 1:1, EtOAc/hexanes, with an initial basewash of the column using hexanes containing 1% Et₃N) to give 20a (0.0606g, 0.162 mmol, 65%, 98% pure by ELSD) as a clear oil that turns to a redoil upon standing: IR (CH₂Cl₂) 3336, 2941, 2891, 2850, 1629, 1523, 1491,1495, 1420, 1254, 1223, 1193, 997, 907, 761, 731 cm⁻¹; ¹H NMR (300 MHz,CDCl₃) δ 7.18 (dd, 2H, J=8.7, 7.5 Hz), 7.04-6.98 (m, 2H), 4.88 (brt, 1H,J=6.0 Hz), 4.44 (d, 2H, J=6.0 Hz), 3.67 (s, 2H), 3.50 (app t, 4H, J=5.0Hz), 2.89 (app t, 4H, J=5.0 Hz), 2.39 (s, 3H), 2.32 (s, 3H), 2.29 (s,3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.0, 159.5, 156.9, 150.9, 132.7, 131.2,126.7, 123.7, 119.1, 110.8, 51.6, 44.4, 43.9, 23.6, 17.8, 11.0, 10.2;HRMS (ESI) m/z calcd for C₁₉H₂₇N₄O₂S ([M+H]⁺) 375.1849, found 375.1845.

1-(o-Tolyl)piperidin-4-yl((((3,5-dimethylisoxazol-4-yl)methyl)thio)methyl)-carbamate(20b). To a solution of2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)acetic acid (3a, 0.0500 g,0.248 mmol) in toluene (4.0 mL) was added DPPA (0.06 mL, 0.261 mmol) andEt₃N (37 μL, 0.261 mmol). The reaction mixture was heated at 110° C. for60 min, cooled to room temperature and treated with a solution of1-(o-tolyl)piperidin-4-ol (4n, 0.0427 g, 0.224 mmol) in CH₂Cl₂ (0.5 mL).The reaction mixture was stirred overnight at 80° C., and diluted withEtOAc and satd. aqueous NH₄Cl. The organic layer was washed with satd.aqueous NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by chromatography on SiO₂ (ISCO, 4 gcolumn, gradient hexanes to 3:7, EtOAc/hexanes, with an initial basewash of the column with hexanes w/ 1% Et₃N) to give 20b (0.0168 g,0.0431 mmol, 17%, 100% pure by ELSD) as a clear oil that eventuallyturned to a light yellow oil upon standing: IR (CH₂Cl₂) 3323, 2947,2924, 2848, 2811, 1711, 1491, 1450, 1422, 1228, 1195, 1027, 762, 723cm⁻¹; ¹H NMR (400 MHz, DMSO-d6) δ 7.98 (t, 1H, J=6.4 Hz), 7.16-7.11 (m,2H), 7.02 (d, 1H, J=7.2 Hz), 6.94 (dt, 1H, J=7.2, 1.2 Hz), 4.72-4.69 (m,1H), 4.15 (d, 2H, J=6.4 Hz), 3.66 (s, 2H), 3.01-2.98 (m, 2H), 2.78-2.72(m, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.04-1.94 (m, 2H),1.77-1.67 (m, 2H); ¹³C NMR (100 MHz, DMSO-d6) δ 165.7, 159.2, 155.5,151.5, 131.8, 130.7, 126.5, 122.8, 118.9, 110.9, 69.9, 49.2, 42.9, 31.6,21.9, 17.4, 10.5, 9.7; HRMS (ESI) m/z calcd for C₂₀H₂₈N₃O₃S ([M+H]⁺)390.1846, found 390.1846.

tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (21a) (WO2012/152854 A1). A solution of nortropinone.HCl (21, 2.00 g, 12.4 mmol)in a minimum amount of water (6.0 mL) was cooled to 0° C., treateddropwise with 1 M NaOH (14.8 mL, 14.8 mmol, 1.2 equiv), warmed to roomtemperature over 20 min, extracted with CH₂Cl₂ (3×40 mL), dried (MgSO₄),filtered, and concentrated in vacuo (water bath at 23° C.) to givenortropinone 21 as the free base (1.54 g, quant.). The colorless oil wasused without further purification.

To a solution of nortropinone 21 (1.54 g, 12.3 mmol) in CH₂Cl₂ (50 mL)cooled to 0° C. was added Boc anhydride (4.26 mL, 18.6 mmol), DMAP(0.302 g, 2.47 mmol), and Et₃N (7.0 mL, 50.2 mmol). The reaction mixturewas allowed to warm to room temperature and stirred overnight. After 19h, the reaction mixture was concentrated in vacuo, and the residue wasdiluted with water, extracted with EtOAc (3×), washed with brine, dried(MgSO₄), filtered, and concentrated in vacuo to give a red sticky solidwhich was purified by chromatography on SiO₂ (CH₂Cl₂) to give 21a (2.18g, 9.68 mmol, 78% over two steps) as a pale yellow oil that solidifiedto an off-white solid upon standing at room temperature: ¹H NMR (300MHz, DMSO-d6) δ 4.34-4.30 (m, 2H), 2.55 (dt, 2H, J=15.6, 4.2 Hz), 2.23(d, 2H, J=15.6 Hz), 2.20 (app s, 1H), 2.03-1.94 (m, 2H), 1.60-1.52 (m,2H), 1.44 (s, 9H); ¹³C NMR (75 MHz, DMSO-d6) δ 207.4, 152.6, 79.2, 52.7,48.1, 28.0 (2 C).

tert-Butyl3-((((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate(22) (WO 2012/152854 A1). A solution of NaHMDS (0.895 g, 4.88 mmol) inTHF (12 mL) was added dropwise (over 10 min) at −78° C. to a solution oftert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (21a, 1.00 g,4.44 mmol) in THF (12 mL). The reaction mixture was stirred at −78° C.for 2 h, treated dropwise (over 20 min) with a solution of PhN(Tf)₂(1.90 g, 5.33 mmol) in THF (12 mL), stirred for an additional 30 min at−78° C. and then allowed to warm to room temperature and stirred for 2h. After addition of 10% aqueous Na₂CO₃ (50 mL), the solution wasextracted with Et₂O (2×75 mL). The combined organic layers were washedwith 10% aqueous Na₂CO₃ solution, dried (MgSO₄), and concentrated invacuo. The crude residue was purified by chromatography on SiO₂ (1:19,EtOAc/hexanes with 1% Et₃N) to give 22 (1.24 g, 3.47 mmol, 78%) as aclear oil that solidified to a wax upon storage at −20° C.: ¹H NMR (400MHz, CDCl₃) δ 6.09 (brs, 1H), 4.54-4.38 (m, 2H), 3.07-3.02 (m, 1H),2.30-2.20 (m, 1H), 2.11-1.99 (m, 3H), 2.00-1.97 (m, 2H), 1.79-1.70 (m,1H), 1.45 (s, 9H).

tert-Butyl 3-(otolyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (23a).A solution of Na₂CO₃ (0.330 g, 3.11 mmol), lithium chloride (0.0600 g,1.41 mmol), tert-butyl3-(((trifluoromethyl)sulfonyl)oxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate(22, 0.460 g, 1.41 mmol) and o-tolylboronic acid (0.235 g, 1.70 mmol) inDME (11 mL) and H₂O (3 mL) was sparged with N₂ for 1 h, and treated withPd(PPh₃)₄ (0.0376 g, 0.0325 mmol). The flask was evacuated andbackfilled with nitrogen (3×) and the mixture was heated at 60° C. for 3h. The mixture was allowed to cool to room temperature, diluted withbrine, extracted with EtOAc (3×), dried (Na₂SO₄), and concentrated invacuo. The resulting brown oil was dry loaded onto SiO₂ and purified bychromatography on SiO₂ (hexanes to 15:1, hexanes/EtOAc) to give 23a(0.330 g, 1.10 mmol, 78%) as a colorless solid: Mp 67.5-68.4° C.; IR(neat) 2975, 2934, 1685, 1420, 1364, 1329, 1169, 1094 cm⁻¹; ¹H NMR (400MHz, CDCl₃, mixture of rotamers) δ 7.20-7.12 (m, 3H), 7.02-7.00 (m, 1H),5.94-5.86 (m, 1H), 4.50-4.30 (m, 2H), 3.11-2.91 (m, 1H), 2.27 (app s,4H), 2.10-1.90 (m, 3H), 1.90-1.80 (m, 1H), 1.50 (s, 9H); ¹³C NMR (100MHz, CDCl₃, 1:1 mixture of rotamers) δ 154.4, 141.6, 136.2, 135.5,134.9, 131.3, 130.8, 130.7, 130.1, 129.3, 128.1, 126.9, 126.8, 125.6,123.5, 120.0, 114.8, 79.3, 53.6, 52.9, 52.7, 52.0, 39.2, 38.4, 34.9,34.3, 30.4, 29.6, 28.4, 19.5, 15.8; HRMS (ESI) m/z calcd for C₁₄H₁₇N([M+H—C₅H₉O₂]⁺) 200.1439, found 200.1435.

2-Chloro-1-(3-(o-tolyl)-8-azabicyclo[3.2.1]octan-8-yl)ethan-1-one (24).A solution of tert-butyl3-(o-tolyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (23a, 0.196 g,0.655 mmol) in EtOH (5.0 mL) was treated with Pd/C (5%, 0.0480 g). Theflask was evacuated and flushed with H₂ (balloon, 3×). The reactionmixture was stirred under H₂ (1 atm, balloon) overnight, filteredthrough Celite, rinsed with EtOH and concentrated in vacuo to give (23,0.160 g, 0.531 mmol, 81%) as a yellow liquid that was used withoutfurther purification.

A solution of 23 (0.200 g, 0.664 mmol) in CH₂Cl₂ (5 mL) was treated atroom temperature with TFA (0.30 mL, 3.98 mmol). After 16 h, the solutionwas concentrated in vacuo. The oily residue was extracted with CH₂Cl₂,washed with satd. aqueous NaHCO₃ and brine, dried (Na₂SO₄), filtered,and concentrated in vacuo to give 3-(o-tolyl)-8-azabicyclo[3.2.1]octane(23b, 0.133 g, 0.661 quant) as a light yellow oil that was used withoutfurther purification.

A solution of 23b (0.130 g, 0.646 mmol) and Et₃N (0.10 mL, 0.710 mmol)in THF (3 mL) was cooled to 0° C. and treated with chloroacetyl chloride(60 μL, 0.710 mmol) dropwise over 1 min. The reaction mixture wasstirred at 0° C. for 1 h and then at room temperature for 20 h. Thesolution was filtered, concentrated in vacuo and the residue wasdissolved in EtOAc, washed with water, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude residue was purified by chromatographyon SiO₂ (1:1, hexanes/EtOAc) to give 24 (0.141 g, 0.508 mmol, 79%) as abrown oil. ¹H NMR analysis indicated an approximately 4:3 ratio of endolexo isomers: ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.09 (m, 6.8H), 4.85-4.80(m, 1H), 4.80-4.74 (m, 0.7H), 4.38-4.30 (m, 1.7H), 4.14-4.04 (m, 3.6H),3.49-3.39 (m, 1H), 2.99-2.88 (m, 0.7H), 2.58-2.49 (m, 1H), 2.38 (s, 3H),2.32 (s, 2H), 2.22-1.70 (m, 11H), 1.55-1.48 (m, 1H); ¹³C NMR (100 MHz,CDCl₃) δ 163.4, 162.1, 141.8, 141.7, 135.9, 135.0, 130.4 (2 C), 126.5,126.4, 126.2, 126.1 (2 C), 126.0, 55.7, 55.4, 52.6, 49.6, 41.5, 41.4,39.5, 39.1, 37.9, 37.5, 32.8, 30.9, 30.3, 29.7, 28.9, 27.1, 19.4, 19.3;HRMS (ESI) m/z calcd for C₁₆H₂₁ClNO ([M+H]⁺), 298.1312, found 298.1301.

2-((((3,5-Dimethylisoxazol-4-yl)methyl)thio)-1-(3-endo-(o-tolyl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone(26a) and2-((((3,5-dimethylisoxazol-4-yl)methyl)thio)-1-(3-exo-(o-tolyl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone(26b). A solution of (3,5-dimethylisoxazol-4-yl)methanethiol (25, 0.0247g, 0.172 mmol) in THF (0.4 mL) was added to a suspension of NaH (60%dispersion in mineral oil, 0.0115 g, 0. mmol) in THF (1.0 mL) at 0° C.The resultant slurry was stirred at 0° C. for 30 min and a solution of2-chloro-1-(3-(o-tolyl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone (24,0.0400 g, 0.144 mmol) in THF (0.4 mL) was added. The reaction mixturewas allowed to warm to room temperature, stirred for 24 h, quenched withbrine (1 mL), diluted with EtOAc (15 mL) and brine (5 mL), and extractedwith EtOAc (2×15 mL). The combined organic layers were dried (Na₂SO₄)and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (3:7, EtOAc/hexanes) to give 26a (16.2 mg, 0.0421mmol, 29%, 99.8% pure by ELSD) and 26b (16.6 mg, 0.0432 mmol, 30%, 100%pure by ELSD) as light yellow oils.

26a (dr 82:18 by ¹H NMR): IR (neat) 2952, 2933, 1629, 1446, 1424, 1195cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.17-7.11 (m, 4H), 4.81-4.80 (m, 1H),4.25-4.24 (m, 1H), 3.72 (s, 2H), 3.46-3.40 (m, 1H), 3.19 (s, 2H), 2.44(brs, 4H), 2.37 (s, 3H), 2.31 (s, 3H), 2.19-2.09 (m, 1H), 2.08-1.84 (m,5H), 1.80-1.66 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 166.8, 164.8, 159.8,141.9, 135.1, 130.5, 126.5, 126.2, 126.0, 109.9, 55.8, 52.2, 39.2, 37.6,32.5, 30.4, 28.9, 27.3, 23.8, 19.3, 11.0, 10.1; HRMS (ESI) m/z calcd forC₂₂H₂₉O₂N₂S ([M+H]⁺) 385.1950, found 385.1946.

26b (dr 92:8 by ¹H NMR): IR (neat) 2952, 2934, 1629, 1489, 1446, 1193,1163 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.20-7.12 (m, 4H), 4.76 (t, 1H,J=7.6 Hz), 4.20 (t, 1H, J=7.6 Hz), 3.80 (d, 1H, J=14.0 Hz), 3.62 (d, 1H,J=14.0 Hz), 3.20 (d, 1H, J=12.8 Hz), 3.10 (d, 1H, J=13.6 Hz), 3.01-2.90(m, 1H), 2.60-2.45 (m, 5H), 2.40 (s, 6H), 2.22-2.11 (m, 1H), 2.10-2.00(m, 1H), 1.85-1.69 (m, 2H), 1.55-1.40 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)δ 166.9, 166.3, 159.8, 142.0, 135.7, 130.4, 126.5, 126.2, 126.0, 109.9,53.3, 49.3, 39.0, 38.0, 32.8, 31.9, 31.1, 29.9, 23.9, 19.5, 11.1, 10.2;HRMS (ESI) m/z calcd for C₂₂H₂₉O₂N₂S ([M+H]⁺) 385.1950, found 385.1944.

(3,5-Dimethylisoxazol-4-yl)methanol (27) (Natale et al., Synth. Commun.1983, 13, 817-822.) To a solution of 3,5-dimethylisoxazole-4-carboxylicacid (1.60 g, 11.3 mmol) in THF (69 mL) at 0° C. was added dropwise a 2M solution of LiAlH₄ in THF (5.6 mL, 11.2 mmol). The reaction mixturewas allowed to warm to room temperature, stirred overnight, transferredto a 500-mL Erlenmeyer flask and treated with sodium sulfate decahydrateuntil the foaming subsided. Celite (2.3 g) was added and the slurry wasfiltered and washed with CH₂Cl₂ (75 mL). The filtrate was concentratedin vacuo to give 27 (1.14 g, 8.97 mmol, 79%) as a clear colorless oil:¹H NMR (400 MHz, CDCl₃) δ 4.46 (s, 2H), 2.38 (s, 3H), 2.29 (s, 3H).

(3,5-Dimethylisoxazol-4-yl)methanethiol (25) (Moreno-Mañas et al., J.Heterocycl. Chem. 1992, 29, 1557-1560.) A solution of(3,5-dimethylisoxazol-4-yl)methanol (27, 0.500 g, 3.90 mmol) in toluene(13 mL) was treated with Lawesson's reagent (0.890 g, 2.15 mmol) at roomtemperature, heated to 80° C. and stirred for 1 d. The crude mixture wasloaded directly onto SiO₂ and purified by chromatography on SiO₂ (4:1,hexanes/EtOAc) to give 25 (0.115 g, 0.803 mmol, 21%) as a light yellowoil: ¹H NMR (300 MHz, CDCl₃) δ 3.49 (d, 2H, J=6.6 Hz), 2.36 (s, 3H),2.30 (s, 3H), 1.64 (t, 1H, J=6.6 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 165.2,159.0, 113.3, 15.9, 10.9, 10.0.

Methyl 2-(phenylthio)acetate (28) (Bahrami et al., J. Org. Chem. 2010,75, 6208-6213.) A solution of thiophenol (0.10 mL, 0.977 mmol), andmethyl bromoacetate (0.164 g, 1.07 mmol) in THF (13 mL) was treated withEt₃N (0.17 mL, 1.17 mmol), stirred at room temperature for 4 h, anddiluted with Et₂O and satd. aqueous NaHCO₃. The aqueous layer wasextracted with Et₂O (2×5 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo to give 28 (0.176 g, 0.966mmol, 99%) as a clear oil: ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.38 (m, 2H),7.33-7.20 (m, 3H), 3.71 (s, 3H), 3.65 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ170.1, 134.9, 129.9, 129.0, 127.0, 52.5, 36.5.

2-(Phenylthio)acetic acid (3d) (Bahrami et al., J. Org. Chem. 2010, 75,6208-6213; Miura et al., Org. Lett. 2001, 3, 2591-2594.) To a solutionof methyl 2-(phenylthio)acetate (28, 0.176 g, 0.966 mmol) in MeOH (2 mL)was added 2 M LiOH (1 mL). The reaction mixture was stirred at roomtemperature for 1 h and TLC analysis (4:1, hexanes/EtOAc) indicated that28 had been consumed. The solution was concentrated in vacuo, dilutedwith water (3 mL) and acidified to pH 2 with 1 M HCl at 0° C. Theaqueous layer was extracted with EtOAc (3×10 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuo to give 3d(0.144 g, 0.857 mmol, 89%) as a colorless solid: ¹H NMR (300 MHz, CDCl₃)δ 11.27 (brs, 1H), 7.43 (d, 2H, J=7.6 Hz), 7.36-7.24 (m, 3H), 3.69 (s,2H); ¹³C NMR (75 MHz, CDCl₃) δ 175.9, 134.4, 130.1, 129.2, 127.2, 36.6.

N,N′-Dimethyl-N-(o-tolyl)ethane-1,2-diamine (4i) (Gruseck et al., Tet.Lett. 1987, 28, 6027-6030.). A microwave vial was flushed with argon andcharged with the N,N′-dimethylethylene-diamine (0.180 g, 2.04 mmol),NaO-t-Bu (0.202 g, 2.04 mmol), (rac)-BINAP (0.0162 g, 0.0260 mmol),Pd₂(dba)₃ (0.0078 g, 0.0085 mmol), degassed toluene (10.2 mL), and2-bromotoluene (0.297 g, 1.70 mmol). The reaction mixture was heated inthe sealed vial under argon at 110° C. for 24 h, cooled to roomtemperature, diluted with CH₂Cl₂, filtered through Celite, andconcentrated in vacuo. The residue was purified by chromatography onbasic Al₂O₃ (95:5, CH₂Cl₂/MeOH) to give 4i (0.0508 g, 0.285 mmol, 17%)as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 7.16 (t, 2H, J=7.6 Hz), 7.08(d, 1H, J=7.6 Hz), 6.98 (d, 1H, J=7.2 Hz), 3.05 (t, 2H, J=6.4 Hz), 2.71(t, 2H, J=6.4 Hz), 2.65 (s, 3H), 2.43 (s, 3H), 2.32 (s, 3H), 1.36 (brs,1H); HRMS (ESI) m/z calcd for C₁₁H₁₉N₂ ([M+H]⁺) 179.1543, found179.1541.

1-(o-Tolyl)piperidin-4-ol (4n) (Harris et al., Org. Lett. 2002, 4,2885-2888.) An oven-dried microwave tube was charged with Pd₂(dba)₃(0.0606 g, 0.0653 mmol), CyJohnphos (0.0292 g, 0.0816 mmol), and4-piperidinol (0.330 g, 3.26 mmol). The microwave tube was evacuated andback-filled with argon. A 1 M solution of LiN(TMS)₂ (1.21 g, 7.17 mmol)in degassed THF (7.2 mL) was added via syringe along with 2-bromotoluene(0.600 g, 3.26 mmol). The reaction vessel was sealed and heated at 65°C. with stirring for 22 h. The reaction mixture was cooled to roomtemperature, quenched with 1 M HCl (10 mL), stirred at room temperaturefor 5 min, neutralized with a satd. aqueous NaHCO₃ solution, and dilutedwith EtOAc. The organic layer was dried (MgSO₄), filtered throughCelite, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (ISCO, 12 g column, gradient hexanes to 3:7,EtOAc/hexanes) to give 4n (0.372 g, 1.94 mmol, 60%) as a brown oil: ¹HNMR (300 MHz, CDCl₃) δ 7.17 (dd, 2H, J=9.3, 7.2 Hz), 7.04-6.96 (m, 2H),3.87-3.81 (m, 1H), 3.15-3.08 (m, 2H), 2.74 (dt, 2H, J=9.6, 2.7 Hz), 2.32(s, 3H), 2.06-2.00 (m, 2H), 1.80-1.69 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ151.9, 132.7, 130.9, 126.4, 123.0, 119.0, 68.0, 49.8, 35.2, 17.7; HRMS(ESI) m/z calcd for C₁₂H₁₈NO ([M+H]⁺) 192.1383, found 192.1307.

tert-Butyl 4-(o-tolyl)-1,4-diazepane-1-carboxylate (29a). A microwavevial was flushed with argon and charged with Boc-homopiperazine (0.223g, 1.10 mmol), NaO-t-Bu (0.116 g, 1.20 mmol), (rac)-BINAP (0.0478 g,0.0752 mmol, 7.5 mol %), Pd₂(dba)₃ (0.0233 g, 0.0251 mmol), degassedtoluene (2.8 mL), and 2-bromotoluene (0.175 g, 1.00 mmol). The reactionmixture was heated in the sealed vial under argon at 80° C. for 19 h,cooled to room temperature, diluted with CH₂Cl₂, filtered throughCelite, and concentrated in vacuo. The residue was purified bychromatography on SiO₂ (1:9, EtOAc/hexanes) to give 29a (0.139 g, 0.479mmol, 48%) as a yellow oil: IR (ATR) 2973, 2828, 1689, 1598, 1491, 1457,1411, 1364, 1233, 1215, 1156, 1122, 878, 761, 725 cm⁻¹; ¹H NMR (500 MHz,CDCl₃, room temperature, mixture of rotamers) δ 7.16 (d, 1H, J=6.0 Hz),7.12 (d, 1H, J=6.0 Hz), 7.04 (d, 1H, J=7.5 Hz), 6.95 (t, 1H, J=7.0 Hz),3.61-3.56 (m, 4H), 3.11-3.04 (m, 4H), 2.31 (s, 3H), 1.96-1.91 (m, 2H),1.49 (s, 9H); ¹³C NMR (100 MHz, CDCl₃, room temperature, mixture ofrotamers) δ 155.6, 155.5, 153.9, 153.8, 132.9, 130.9, 126.5, 123.1,120.8 (2 C), 79.3, 56.2, 56.0, 55.5, 55.2, 48.4, 48.0, 46.2, 45.4, 29.0,28.9, 28.5, 18.5; HRMS (ESI) m/z calcd for C₁₇H₂₇N₂O₂ ([M+H]⁺) 291.2067,found 291.2062.

(3S,5R)-3,5-Dimethyl-1-(o-tolyl)piperazine (4k) (WO 2015/042297 A1). ASchlenk flask was flushed with N₂ and charged withcis-2,6-dimethylpiperazine (0.110 g, 0.963 mmol), NaO-t-Bu (0.170 g,1.75 mmol), (rac)-BINAP (0.0084 g, 0.0130 mmol), Pd₂(dba)₃ (0.0083 g,0.0087 mmol), degassed toluene (4 mL), and 2-bromotoluene (0.150 g,0.880 mmol). The reaction mixture was heated under N₂ at 110° C. for 24h, cooled to room temperature, diluted with CH₂Cl₂, filtered throughCelite, and concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (1:19, MeOH/CH₂Cl₂) to give 4k (0.140 g, 0.685mmol, 78%) as clear, yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.19-7.15 (m,2H), 7.02-6.98 (m, 2H), 3.13-3.10 (m, 2H), 3.01 (app d, 2H, J=10.5 Hz),2.35-2.31 (m, 5H), 1.12 (d, 6H, J=6.5 Hz).

tert-Butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (30) (Jacobsenet al., J. Med. Chem. 1999, 42, 1123-1144.) To a solution ofcis-2,6-dimethylpiperazine (0.500 g, 4.38 mmol) in CH₂Cl₂ (11 mL) at 0°C. was added dropwise a solution of Boc-anhydride (0.946 g, 4.33 mmol)in CH₂Cl₂ (2.6 mL). The reaction mixture was allowed to warm to roomtemperature, stirred overnight, diluted with CH₂Cl₂ and washed withsatd. aqueous Na₂CO₃ solution. The aqueous layer was extracted withCH₂Cl₂. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated in vacuo to give 30 (0.813 g, 3.79mmol, 87%) as an off-white solid: ¹H NMR (300 MHz, CDCl₃) δ 4.10-3.80(m, 2H), 2.85-2.70 (m, 2H), 2.40-2.20 (m, 2H), 1.46 (s, 9H), 1.05 (d,6H, J=6.3 Hz).

tert-Butyl (3R,5S)-3,5-dimethyl-4-phenylpiperazine-1-carboxylate (29b).To a sealed tube under an argon atmosphere was added a solution of KHMDS(0.241 g, 1.15 mmol) in dry 1,4-dioxane (2.0 mL), a solution oftert-butyl 3,5-dimethylpiperazine-1-carboxylate (30, 0.246 g, 1.15 mmol)in dry 1,4-dioxane (0.9 mL) and bromobenzene (100 μL 0.955 mmol). Thereaction mixture was stirred at 100° C. for 18 h, cooled to roomtemperature, quenched with water (5 mL), diluted with Et₂O (15 mL) andthe aqueous layer was extracted with Et₂O (2×15 mL). The combinedorganic layers were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude residue was purified by chromatographyon SiO₂ (1:9, EtOAc/hexanes) to give 29b (0.0970 g, 0.334 mmol, 35%) asa colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.33-7.27 (m, 2H), 7.15-7.09(m, 3H), 4.00-3.80 (m, 2H), 3.07-3.03 (m, 2H), 2.82 (brt, 2H, J=11.7Hz), 1.50 (s, 9H), 0.77 (d, 6H, J=6.3 Hz).

tert-Butyl 3,5-dimethyl-4-(m-tolybpiperazine-1-carboxylate (29c). Asealed tube under an argon atmosphere was treated with KHMDS (0.221 g,1.05 mmol) in dry 1,4-dioxane (2.0 mL), a solution of tert-butyl3,5-dimethylpiperazine-1-carboxylate (30, 0.226 g, 1.05 mmol) in dry1,4-dioxane (0.7 mL) and bromotoluene (105 μL 0.877 mmol). The reactionmixture was stirred at 100° C. for 18 h, cooled to room temperature,quenched with water (5 mL), diluted with Et₂O (15 mL) and the aqueouslayer was extracted with Et₂O (2×15 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The crude residue was purified by chromatography on SiO₂ (1:9,EtOAc/hexanes) to give 29c (0.0441 g, 0.145 mmol, 17%) as a colorlessoil: ¹H NMR (300 MHz, CDCl₃) δ 7.18 (t, 1H, J=7.5 Hz), 6.96-6.89 (m,3H), 4.00-3.80 (m, 2H), 3.06-3.00 (m, 2H), 2.81 (brt, 2H, J=11.7 Hz),2.32 (s, 3H), 1.50 (s, 9H), 0.77 (d, 6H, J=6.3 Hz).

Example 2 Synthesis and Characterization of(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl)methanone(JJ-450)

((4-Fluorophenyl)ethynyl)trimethylsilane (Everett et al., Org. Lett.2013, 15, 2926-2929; Yonemoto-Kobayashi et al., Org. Biomol. Chem. 2013,11, 3773-3775). A flame-dried flask under Ar was charged withPd(PPh)₂Cl₂ (0.361 g, 0.514 mmol), Cud (0.0979 g, 0.514 mmol), and4-fluorobromobenzene (5.66 mL, 51.4 mmol). Et₃N (110 mL) and(trimethylsilyl)acetylene (10.9 mL, 77.1 mmol) were added via syringeand the solution was sparged with Ar for 30 min. The reaction mixturewas heated to 80° C. overnight and analysis by TLC (4:1, hexanes/EtOAc)indicated that 4-fluorobromobenzene had been consumed. The solution wascooled to room temperature and filtered through celite. The celite waswashed (Et₂O) until the washes appeared colorless. The combinedfiltrates were concentrated in vacuo. The crude residue was purified bychromatography on SiO₂ (hexanes) to afford4-fluorophenyl)ethynyl)trimethylsilane (9.03 g, 47.0 mmol, 91%) as apale orange oil: ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 6.99 (t,2H, J=8.7 Hz), 0.25 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 162.6 (d,J_(C-F)=248 Hz), 133.9 (d, J_(C-F)=8 Hz), 119.3 (d, J_(C-F)=4 Hz), 115.5(d, J_(C-F)=22 Hz), 104.0, 93.8, −0.07.

3-(4-Fluorophenyl)propiolic acid (Yonemoto-Kobayashi et al., Org.Biomol. Chem. 2013, 11, 3773-3775). CsF (4.74 g, 31.2 mmol) was loadedinto an oven-dried 250-mL round bottom flask in a glovebox. The flaskwas removed from the glovebox, attached to a CO₂ balloon, equipped witha magnetic stirrer and a septum, and filled with anhydrous DMSO (60 mL).Neat ((4-fluorophenyl)ethynyl)trimethylsilane (5.00 g, 26.0 mmol) wasadded dropwise. The reaction mixture was stirred under CO₂ at roomtemperature overnight, diluted with water (600 mL) and washed withCH₂Cl₂ (2×150 mL). The aqueous layer was acidified at 0° C. to pH 1 with6 M HCl and then extracted with Et₂O (3×200 mL). The combined organiclayers were dried (MgSO₄), filtered, and concentrated in vacuo to afford3-(4-fluorophenyl)propiolic acid (3.02 g, 18.4 mmol, 71%) as an orangesolid: ¹H NMR (400 MHz, Acetone-d₆) δ 11.74 (brs, 1H), 7.71 (dd, 2H,J=8.6, 5.6 Hz), 7.26 (t, 2H, J=8.6 Hz); ¹³C NMR (100 MHz, Acetone-d₆) δ164.8 (d, J_(C-F)=249 Hz), 154.7, 136.1 (d, J_(C-F)=9 Hz), 117.1 (d,J_(C-F)=23 Hz), 84.6, 81.8.

1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one.To a solution of 3-(4-fluorophenyl)propiolic acid (3.00 g, 18.3 mmol) inanhydrous CH₂Cl₂ (180 mL) at 0° C. was added1-(5-chloro-2-methylphenyl)piperazine (4.62 g, 21.9 mmol), and Et₃N(6.35 mL, 45.7 mmol), followed by dropwise addition of T3P (50 wt. %solution in EtOAc, 19.4 mL, 27.4 mmol). The reaction mixture was stirredat 0° C. for 30 min, warmed to room temperature overnight, diluted withCH₂Cl₂ (200 mL), washed with 1 M HCl (150 mL), dried (MgSO₄), filtered,and concentrated in vacuo. The residue was purified by chromatography onSiO₂ (2:1, hexanes/EtOAc) to give1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(5.22 g, 14.6 mmol, 80%) as an off white solid: Mp 138.7-140.4° C.; IR(neat) 2924, 2216, 1625, 1596, 1504, 1443, 1431, 1219, 1038, 837 cm⁻¹;¹H NMR (300 MHz, CDCl₃) δ 7.55 (dd, 2H, J=7.5, 5.4 Hz), 7.12-6.94 (m,5H), 3.96 (app t, 2H, J=4.8 Hz), 3.82 (app t, 2H, J=4.8 Hz), 2.95 (appt, 2H, J=4.8 Hz), 2.87 (app t, 2H, J=4.8 Hz), 2.28 (s, 3H); ¹³C NMR (75MHz, CDCl₃) δ 163.5 (d, J_(C-F)=251 Hz), 153.0, 151.7, 134.5 (d,J_(C-F)=9 Hz), 132.1, 131.8, 130.9, 123.7, 119.8, 116.4 (d, J_(C-F)=4Hz), 116.0 (d, J_(C-F)=23 Hz), 89.9, 80.9, 51.9, 51.3, 47.4, 41.8, 17.3;HRMS (ESI) m/z calcd for C₂₀H₁₉ClFON₂ ([M+H]⁺) 357.1164, found 357.1165.

(Z)-1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one.To a solution of1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(5.00 g, 14.0 mmol) in dry EtOAc (140 mL) was added Lindlar's catalyst(5% Pd on CaCO₃, lead poisoned, 0.298 g, equivalent to 1 mol % Pd) andquinoline (0.83 mL, 7.01 mmol). The reaction vessel was placed undervacuum, backfilled with H₂ (balloon, 2×) and allowed to stir at roomtemperature for 6 h. Analysis by TLC (2:1, hexanes/EtOAc) indicated that1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-onehad been mostly consumed. The reaction mixture was filtered throughCelite, washed with EtOAc, and concentrated under vacuum. The combinedorganic layers were washed with 1 M HCl, dried (MgSO₄), filtered, andconcentrated in vacuo. The crude material was purified by chromatographyon SiO₂ (1:1, hexanes/EtOAc) to afford(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one(3.15 g, 8.78 mmol, 63%, 87% brsm) as a colorless solid: IR (neat) 2913,2239, 1616, 1506, 1437, 1223, 837, 725 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.41-7.36 (m, 2H), 7.08-7.02 (m, 3H), 6.96 (dd, 1H, J=8.1, 2.1 Hz), 6.80(d, 1H, J=2.1 Hz), 6.66 (d, 1 H J=12.5 Hz), 6.05 (d, 1H, J=12.5 Hz),3.80 (m, 2H, J=5.0 Hz), 3.49 (t, 2H, J=5.0 Hz), 2.80 (t, 2H, J=5.0 Hz),2.53 (t, 2H, J=5.0 Hz), 2.21 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.3,162.7 (d, J_(C-F)=248 Hz), 151.7, 132.6, 132.0, 131.8, 131.5 (d,J_(C-F)=3 Hz), 132.1, 131.8, 130.9, 130.2 (d, J_(C-F)=8 Hz), 123.6,122.7, 119.6, 115.6 (d, J_(C-F)=21 Hz), 51.4, 51.2, 46.5, 41.5, 17.3;HRMS (ESI) m/z calcd for C₂₀H₂₁ClFON₂ ([M+H]⁺) 359.1321, found 359.1329.

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl)-methanone(JJ-450). THF (90 mL) was degassed by sparging with Ar for 60 min andtreated at room temperature under Ar atmosphere with anhydrous CrCl₂(6.43 g, 51.8 mmol) followed by(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one(3.10 g, 8.64 mmol) and CH₂ICl (3.36 mL, 43.2 mmol). The reactionmixture was stirred for 20 h at 80° C., cooled to room temperature,quenched by the addition of 1.0 M aqueous HCl (300 mL) and extractedwith EtOAc (3×300 mL). The combined organic layers were filtered througha plug of basic Al₂O₃, and concentrated in vacuo. The residue waspurified by chromatography on SiO₂ (1:1, hexanes/EtOAc) to afford an oilthat was further purified twice by chromatography on basic Al₂O₃ (1:1,hexanes/EtOAc) to give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl)methanone(2.76 g, 7.41 mmol, 86%) as a clear oil that solidified after storage onhigh vacuum overnight: Mp 78.2-80.4° C. (hexanes); IR (CH₂Cl₂) 2936,1637, 1592, 1510, 1487, 1435, 1223, 1033, 837, 815 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.16-7.11 (m, 2H), 7.07 (dd, 1H, J=8.1, 0.5 Hz), 7.00-6.94(m, 3H), 6.73 (d, 1H, J=2.1 Hz), 3.81-3.76 (m, 1H), 3.71-3.60 (m, 2H),3.36 (ddd, 1H, J=12.4, 8.8, 3.1 Hz), 2.79-2.71 (m, 2H), 2.45 (td, 1H,J=8.8, 7.0 Hz), 2.35-2.29 (m, 1H), 2.26-2.16 (m, 5H), 1.83 (dt, 1H,J=7.0, 5.6 Hz), 1.35 (td, 1H, J=8.8, 5.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ167.2, 161.7 (d, J_(C-F)=244 Hz), 151.9, 133.1 (d, J_(C-F)=3 Hz), 131.9(d, J_(C-F)=14 Hz), 130.9, 129.1 (d, J_(C-F)=8 Hz), 123.6, 119.7, 115.0(d, J_(C-F)=21 Hz), 51.8, 51.6, 45.6, 42.2, 23.8, 23.5, 17.3, 10.7; HRMS(ESI) m/z calcd for C₂₁H₂₃ClFON₂ ([M+H]⁺) 373.1477, found 373.1478.

Racemic JJ-450 was separated on a SFC Chiralpak-IC semiprep (250×10 mm)column (20% MeOH, 6 mL/min, 220 nM, P=100) to afford(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1S,2R)-2-(4-fluorophenyl)cyclopropyl)methanoneJJ-450A (retention time 13.1 min) as a colorless viscous oil (100%purity by ELSD): [α]²⁰ _(D)−118.7 (c 0.39, CDCl₃); ¹H NMR (300 MHz,CDCl₃) δ 7.17-7.10 (m, 2H), 7.07 (d, 1H, J=8.1 Hz), 7.02-6.94 (m, 3H),6.72 (d, 1 H J=2.1 Hz), 3.83-3.75 (m, 1H), 3.72-3.58 (m, 2H), 3.39-3.31(m, 1H), 2.81-2.69 (m, 2H), 2.45 (td, 1H, J=8.7, 6.9 Hz), 2.36-2.25 (m,1H), 2.25-2.15 (m, 5H), 1.83 (dt, 1H, J=6.9, 5.5 Hz), 1.35 (td, 1H,J=8.7, 5.5 Hz); HRMS (ESI) m/z calcd for C₂₁H₂₃ClFON₂ ([M+H]⁺) 373.1477,found 373.1476. The enantiomeric excess was 100% ee (SFC Chiralpak-IC(250×4.6 mm); 20% MeOH, 220 nM, 2 mL/min; retention time: 9.8 min).

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1R,2S)-2-(4-fluorophenyl)cyclopropyl)-methanoneJJ-450B (retention time 16.5 min) was obtained as a colorless viscousoil (100% purity by ELSD): [α]²⁰ _(D)+117.4 (c 0.38, CDCl₃); ¹H NMR (300MHz, CDCl₃) δ 7.17-7.10 (m, 2H), 7.07 (d, 1H, J=8.1Hz), 7.01-6.94 (m,3H), 6.72 (d, 1H, J=2.1 Hz), 3.82-3.74 (m, 1H), 3.71-3.60 (m, 2H),3.39-3.30 (m, 1H), 2.81-2.68 (m, 2H), 2.45 (td, 1H, J=8.6, 7.0 Hz),2.35-2.26 (m, 1H), 2.25-2.15 (m, 5H), 1.83 (dt, 1H, J=7.0, 5.6 Hz), 1.35(td, 1H, J=8.6, 5.6 Hz); HRMS (ESI) m/z calcd for C₂₁H₂₃ClFON₂ ([M+H]⁺)373.1477, found 373.1476. The enantiomeric excess was 100% ee (SFCChiralpak-IC (250×4.6 mm); 20% MeOH, 220 nM, 2 mL/min; retention time:12 min).

Example 3 Activity of Compounds in PSA Luciferase Assay

The biological activity of analogs 5-16, 18, 20, 26, JJ-450, and theresolved enantiomers JJ-450A and J-450B was determined and compared toHTS hit 1 (IC₅₀ 7.3 μM) and MDV3100 (IC₅₀ 1.1 μM) using the Dual-Gloluciferase system (Promega, WI, USA) in C4-2-PSA-rl cells, which weregenerated by transfection with PSA6.1-luc and pRL-TK followed by stableselection using G418 and puromycin. C4-2-PSA-rl stable cells werecultured in RPMI 1640 medium with 10% FBS, 1% penicillin-streptomycin,1% L-glutamine, 10 mg/mL puromycin, and 50 mg/mL G418. C4-2-PSA-rl cellswere seeded in 24-well plates such that they reached 75-80% cellmonolayer density after 24 h. C4-2-PSA-rl cells were then treated for 24h with 0, 0.2, 0.8, 3.2, 12.8, or 25 nM of each compound dissolved inDMSO (0.8% DMSO/well) in the presence of 1 nM synthetic androgen R1881,with each experimental condition in triplicate. The cells were alsotreated in parallel with 12.8 μM compound 1 and 12.8 μM MDV3100 aspositive controls. Each compound was tested in at least two independentexperiments. Luciferase activity was assayed using the Dual-Luciferase®Reporter Assay System (Promega) using LMax II Microplate Reader(Molecular Devices). The luciferase assay results were acquired usingSoftMax Pro5.45 software (Molecular Devices) and analyzed using GraphPadPrism. PSA6.1-luc activity was normalized to the Renilla luciferaseactivity. Relative luciferase activity was calculated as the quotient ofandrogen-induced PSA-firefly/Renilla luciferase activity. Since PSApromoter activity correlates to AR transcriptional activity, inhibitionof AR will result in decreased PSA-luciferase activity. IC₅₀ values werecalculated using GraphPad Prism and data represent the mean and SD of2-6 independent experiments (Table 2).

TABLE 2 In vitro activity of analogs in the PSA luciferase assay inC4-2-PSA-rl cells. Entry Compound IC₅₀ (μM) 1  1  7.3 ± 2.5^(c) 2  5a>25^(a) 3  5b 14.5 ± 3.2^(b) 4  5c >25^(a) 5  5d >25^(a) 6  5e 12.0 ±1.6^(b) 7  5f 12.6 ± 7.7^(b) 8  5g 11.1 ± 5.3^(b) 9  5h >25^(a) 10  5i18.4 ± 9.2^(b) 11  5j 11.1 ± 3.3^(a) 12  5k  3.1 ± 1.1^(a) 13  5l 14.7 ±4.4^(a) 14  5m 16.6 ± 4.8^(b) 15  6 10.8 ± 5.7^(b) 16  7 13.7 ± 0.8^(b)17  8 14.4 ± 3.7^(b) 18  9 >25^(a) 19 10 20.3 ± 11.6^(a) 20 11 >25^(a)21 12 >25^(b) 22 13 16.1 ± 3.3^(b) 23 14 12.7 ± 0.8^(a) 24 15  2.9 ±1.0^(b) 25 16 >25^(b) 26 18a >25^(b) 27 18b >25^(b) 28 18c  7.2 ±2.7^(c) 29 20a >25^(a) 30 20b >25^(c) 31 26a  7.7 ± 1.6^(b) 32 26b  7.9± 2.8^(a) 33 JJ-450  2.7 ± 1.1 34 JJ-450A  1.6 ± 0.1 35 JJ-450B 13.1 ±1.8 36 MDV3100  1.1 ± 0.5^(e) Assay repeats: ^(a)n = 2; ^(b)n = 3; ^(c)n= 4; ^(d)n = 5; ^(e)n = 6.

Modifications of the substituents on the benzene ring in zone 1 revealedthat methyl groups in the 3- and 4-positions (5c, 5d) led to loss ofactivity, while the 2-methyl analog 5b (IC₅₀ 14.5 μM) retained abouthalf of the activity of the 2,3-dimethylated 1 (Table 2). Removal of the2-methyl group in 5a deleted activity. In agreement with this trend inzone 1, the bulky 1-naphthyl substituent (5g) recovered activity (IC₅₀11.1 μM). Analogs with electron-withdrawing substituents at the benzene2-position (2-NC, 5e, and 2-F, 5f) also maintained or slightly increasedactivity (IC₅₀ 12-13 μM); however, the electron-donating 2-methoxysubstituted 5h was not tolerated and resulted in a complete loss ofactivity, possibly due to an increase in the pKa of the aniline and/oran unfavorable increase in the π-electron density of the aromatic ring.

The piperazine core (zone 2) was queried through substitutions withflexible as well as constrained acyclic and cyclic diamines. Theflexible N,N′-dimethylethylenediamine linker in 5i (IC₅₀ 18.4 μM) andthe 7-membered diazepane 5j (IC₅₀ 11.1 μM) both conserved activity. Thedimethylated piperazines 5l and 5m (IC₅₀ 15-17 μM) were both also almostas active as the initial hit. In contrast, the conformationally morehighly constraint 2,6-dimethylpiperazine 5k was considerably more activewith an IC₅₀ of 3.1 μM. Installment of an ethylene bridge and acarbon-linked (2-Me)Ph group decreased activity again, since bothdiastereomers of the bicyclo[3.2.1] ring systems 26a and 26b, showed anIC₅₀ of 8 μM.

Reduction of amide 5b to amine 6 resulted in a 1.3-fold increase inactivity to an IC₅₀ of 10.8 μM. Sulfonamide 18c (IC₅₀ 7.2 μM) was twiceas active as the initial hit 1, but urea 20a and carbamate 20b wereinactive.

The replacement of the thioether linkage in zone 2 with an ether groupabolished activity in 18a. Substituting the thioether with theN-methylated amine in 18b also abolished activity. In contrast, in ananalogous system with a phenyl group in place of the isoxazole, boththioether 7 as well as the all-carbon chain containing 8 showed constantactivity (IC₅₀˜14 μM).

In order to verify that the biological effect in the thioether serieswas not a result of S-oxidation in the cellular assay, common productsof thioether oxidation, i.e. sulfoxide 12 and sulfone 13, were tested.While sulfone 13 retained some activity (IC₅₀ 16.1 μM), sulfoxide 12 wasinactive. Shortening the three-atom chain to afford the two-atomthioether-linked 9 also abolished activity. The rigidified alkyne 10 andthe corresponding (E)-alkene 11 and its cyclopropane isostere 16 werealso found to be essentially inactive. In contrast, the (Z)-alkene 14surprisingly showed an IC₅₀ of 12.7 μM, and the corresponding cis-fusedcyclopropane isostere 15 was even more potent than analog 1, showing anIC₅₀ of 2.9 μM (Table 2).

In summary, zone 1 modifications showed that the ortho-substituent onthe phenyl ring was important for activity. In zone 2, the stericallyencumbered 2,6-dimethylpiperazine proved superior to flexible,unsubstituted, and bridged analogs. In zone 3, a carbonyl group was notrequired, and a sulfonamide and even the reduced amine were welltolerated. In zone 4, thioether oxidation reduces activity, and only thecis-cyclopropane successfully and significantly improves the IC₅₀Limited substitutions were performed in zone 5, but in general analogswith a phenyl group were equipotent with their 3,5-dimethylisoxazolecongeners (see, for example, 7 vs 5b). Compounds 5k, 15, and JJ-450(particularly JJ-450A) were found to be significantly more potentthan 1. Compounds 15 and JJ-450 are of particular interest due to theisosteric replacement of the thioether linker with the metabolicallymore stable cyclopropane.

Compounds 559, 562, 475, 476, 484, and 458 are all also active in thePSA luciferase assay at sub-micromolar EC50s (450-900 nM), and they areinactive against androgen receptor (AR) negative cell lines in cellproliferation assays.

Additional compounds are shown below:

Compound #583 is very potent, with an IC₅₀>1 uM in inhibitingAR-dependent PSA promoter activity (FIG. 10A). As expected, #583inhibited proliferation of AR-positive C4-2 (FIG. 10B), but notAR-negative PC3 (FIG. 10C), prostate cancer cells. Also, #583 does notcontain a sulfur atom in the structure and should therefore be moreresistant to oxidative metabolic degradation than the sulfur-containingcompounds.

Compounds #571 and #425 were developed for conjugation to agarosematrix. #571 is quite active, with an IC50 of ˜3 uM in the inhibition ofAR activation of PSA promoter in a luciferase assay (FIG. 11).

Example 4 Inhibition of Xenograft Tumor Growth by JJ-450

22Rv1 xenograft tumors were established in SCID mice by subcutaneousinjection of 2×10⁶ cells in Matrigel. Once the tumors reached ˜150 μL involume, the mice were castrated and randomized into 3 groups for dailyIP injection of vehicle (n=11), 10 mg/kg (n=11) and 75 mg/kg (n=11)groups. Injection of JJ-450 was initiated at time of castration. Tumorvolumes were measured 3 times every week. As shown in FIG. 12, compoundJJ-450 significantly inhibited tumor growth. Error bars, SEM.

LNCaP xenograft tumors were established in SCID mice by subcutaneousinjection of 2×10⁶ cells in Matrigel. Once the tumors reached ˜200 ul involume, the mice were castrated and randomized into 4 groups: oralgavage of vehicle (n=6), oral gavage at 10 mg/kg (n=6), IP injection at10 mg/kg (n=8), and oral gavage at 75 mg/kg (n=7) groups. Administrationof JJ-450 was started 2 weeks after castration. Tumor volumes weremeasured twice every week. As shown in FIG. 13, compound JJ-450significantly inhibited tumor growth. Error bars, SEM.

Example 5 Synthesis and Characterization of Additional Analogs General:

All glassware was flame-dried or dried in an oven at 120° C. for morethan two hours prior to use. All air- and moisture-sensitive reactionswere performed under N₂ or Ar atmosphere. Reactions carried out at 0° C.or −78° C. employed an ice bath or an acetone/dry ice bath.Tetrahydrofuran and diethyl ether were either distilled oversodium/benzophenone ketyl, CH₂Cl₂ and toluene were distilled from CaH₂.All other materials were obtained from commercial sources and used asreceived. Infrared spectra were determined neat on a Smiths DetectionIdentify IR FT-IR spectrometer. ¹H and ¹³C NMR spectra were obtained ona Bruker Advance 300 MHz, 400 MHz or 500 MHz NMR in CDCl₃ unlessotherwise specified. Chemical shifts (δ) were reported in parts permillion, with the residual solvent peak used as an internal standard δ¹H/¹³C (Solvent); 7.26/77.00 (CDCl₃), 2.50/39.50 (DMSO-d6); they aretabulated as follows: chemical shift, multiplicity (s=singlet, brs=broadsinglet, d=doublet, brd=broad doublet, t=triplet, brt=broad triplet,q=quartet, m=multiplet), number of protons, and coupling constant(s).¹³C NMR spectra were obtained at 75 MHz, 100 MHz or 125 MHz unlessotherwise specified using a proton-decoupled pulse sequence and aretabulated by observed peak. ¹⁹F spectra were obtained at 471 MHz or 376MHz unless otherwise specified using a proton-decoupled pulse sequenceand are tabulated by observed peak. Reactions were monitored bythin-layer chromatography analysis using pre-coated silica gel 60 F254plates (EMD, 250 μm thickness), and visualization was accomplished witha 254 nm UV light. Flash chromatography was performed using SiO₂(Silicycle, Silia-P Flash Silica Gel, 40-63 μm).

FIGS. 14-35 provide exemplary reaction schemes for several of theanalogs described in detail below. FIG. 14 is a general reaction schemefor propiolic acid precursor compounds. FIG. 15 is a reaction scheme for(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)-cyclopropyl-1,2-d2)-methanone.FIG. 16 shows three general reaction schemes for several precursorcompounds including aryl and piperazinyl moieties. FIG. 17 is a generalreaction scheme for several analogs comprising cyclopropyl andpiperazinyl moieties. FIG. 18 is a reaction scheme for(4-(5-chloro-2-fluorobenzoyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanoneand(4-((5-chloro-2-fluorophenyl)-sulfonyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone.FIG. 19 is a reaction scheme for(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)(2-(4-fluorophenyl)cyclopropyl)-methanone.FIG. 20 is a reaction scheme for(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone.FIG. 21 is a reaction scheme for(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanone.FIG. 22 is a reaction scheme for3-fluoro-2-(4-(2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile.FIG. 23 is a reaction scheme for(4-(2-chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone.FIG. 24 is a reaction scheme for(4-cyclohexyl-piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanoneand(4-(Tetrahydro-2H-pyran-4-yl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone.FIG. 26 is a reaction scheme for(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(4-(4-(trifluoromethyl)phenyl)oxetan-2-yl)methanone.FIG. 27 is a reaction scheme fortrans-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)-cyclopropyl)methanone.FIG. 28 is a reaction scheme forcis-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)cyclopropyl)-methanone.FIG. 29 is a reaction scheme for cis- andtrans-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(2-(4-fluorophenyl)-1-(trifluoromethyl)-cyclopropyl)methanone.FIG. 30 is a reaction scheme fortrans-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2RS)-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropyl)-methanone.FIG. 31 is a reaction scheme fortrans-(4-(2,5-bis(trifluoromethyl)phenyl)-piperazin-1-yl)(1-(trifluoromethyl)-2-(4-(trifluoromethyl)-phenyl)cyclopropyl)methanone.FIG. 32 is a reaction scheme forcis-((1SR,3RS)-2,2-difluoro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone.FIG. 33 is a reaction scheme for(4-(5-chloro-2-(trifluoromethyl)-phenyl)piperazin-1-yl)(3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)methanone.FIG. 34 is a reaction scheme for(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(3-(4-(trifluoromethyl)phenyl)bicyclo[1.1.0]butan-1-yl)methanone.FIG. 35 is a reaction scheme for(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)(3-(4-(trifluoromethyl)phenyl)cyclobutyl)-methanone.

3-(3-(Trifluoromethyl)phenyl)propiolic acid (Yonemoto-Kobayashi et al.,Org. & Biomolec. Chem. 2013, 11:3773-3775; Solomon et al., JACS 1963,85:3492-3496; Austin et al., J. Org. Chem. 1981, 46:2280-2286. Asolution of Pd(PPh₃)₂Cl₂ (0.0134 g, 0.0436 mmol), CuI (0.00829 g, 0.0436mmol), and 3-bromobenzo-triflouride (0.62 mL, 4.36 mol) in Et₃N (8.7 mL)was sparged with Ar for 15 min and treated with(trimethylsilyl)acetylene (0.93 mL, 6.53 mmol) and sparged for anadditional 2 min. The resulting mixture was heated to 80° C. overnight,cooled to rt, filtered through Celite, washed (Et₂O) until the washesappeared colorless and the filtrate was concentrated under reducedpressure. The crude residue was purified by chromatography on SiO₂(hexanes) to give thetrimethyl((3-(trifluoromethyl)phenyl)ethynyl)silane (1.03 g, 4.24 mmol,97%) as a pale yellow oil.

A solution of CsF (0.775 g, 5.10 mmol) in dry DMSO (6.5 mL) under anatmosphere of CO₂ (balloon) at rt was treated with a solution oftrimethyl((3-(trifluoromethyl)phenyl)ethynyl)silane (1.03 g, 4.25 mmol)dropwise and the reaction was stirred under CO₂ at rt overnight. Thereaction mixture was diluted with H₂O (80 mL) and extracted with CH₂Cl₂(2×25 mL). The aqueous layer was acidified (>pH 1) with 6 M aqueous HClat 0° C. and extracted with Et₂O (3×25 mL). The combined organic layerswere dried (MgSO₄), concentrated under reduced pressure, and dried underhigh vacuum to give 3-(3-(trifluoromethyl)phenyl)propiolic acid (0.774g, 3.62 mmol, 85%) as an pale tan orange waxy solid: ¹H NMR (400 MHz,Acetone-d₆) δ 11.85 (bs, 1H), 7.95-7.87 (m, 3H), 7.36 (t, J=7.4 Hz, 1H);¹³C NMR (100 MHz, Acetone-d₆) δ 154.3, 137.1, 131.7 (q, J_(CF)=33.0 Hz),130.0 (q, J_(CF)=3.8 Hz), 128.1 (q, J_(CF)=3.4 Hz), 124.5 (q,J_(CF)=272.0 Hz), 121.7, 83.6, 82.9.

Trimethyl((4-(pentafluoro-λ6-sulfaneyl)phenyl)ethynyl)silane. A solutionof Pd(PPh₃)₂Cl₂ (0.0365 g, 0.0519 mmol), CuI (0.0100 g, 0.0519 mmol),and (4-bromophenyl)pentafluoro-6-sulfane (1.50 g, 5.19 mmol) in Et₃N (11mL) was sparged with Ar for 10 min, treated with(trimethylsilyl)acetylene (1.10 mL, 7.79 mmol), sparged with Ar for 5min, heated to 80° C. for 22 h, cooled to rt, filtered through Celite,washed (Et₂O) until the washes appeared colorless, and the combinedfiltrates were concentrated under reduced pressure. The crude residuewas purified by chromatography on SiO₂ (hexanes) to givetrimethyl((4-(pentafluoro-λ6-sulfaneyl)phenyl)ethynyl)silane (1.32 g,4.40 mmol, 85%) as a pale yellow oil: IR (CH₂Cl₂) 2963, 2165, 1599,1493, 1401, 1251, 1095, 826, 802, 759 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.68 (dt, J=9.0, 2.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 0.28 (s, 9H); ¹³CNMR (100 MHz, CDCl₃) δ 153.2 (quint, J_(CF)=18.0 Hz), 126.9, 125.9(quint, J_(CF)=5.0 Hz), 102.7, 98.0, −0.3; ¹⁹F NMR (376 MHz, CDCl₃) δ84.0 (quint, J=150.2 Hz, 1 F), 62.6 (d, J=150.2 Hz, 4 F); HRMS (ESI) m/zcalcd for C₁₁H₁₃F₅SiS ([M]⁺) 300.0427, found 300.0400.

3-(4-(Pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid. A solution of CsF(0.801 g, 5.27 mmol) in dry DMSO (3 mL) under CO₂ (balloon) at rt wastreated with a solution oftrimethyl((4-(pentafluoro-λ6-sulfaneyl)phenyl)ethynyl)silane (1.32 g,4.40 mmol) in DMSO (5.8 mL) dropwise and the reaction was stirred underCO₂ at rt overnight, diluted with H₂O (90 mL) and extracted with CH₂Cl₂(2×50 mL). The aqueous layer was acidified (>pH 1) with 6 M aqueous HClat 0° C. and extracted with Et₂O (3×50 mL). The combined organic layerswere washed with H₂O (50 mL), dried (MgSO₄), concentrated under reducedpressure, and dried under high vacuum to give3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid (0.338 g, 1.24mmol, 28%) as brown solid. Mp 156.5-159.6° C.; IR (CDCl₃) 2979, 2876,2577, 2235, 1677, 1416, 1298, 1217, 886, 829, 751 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 10.00 (bs, 1H), 7.82 (dt, J=9.0, 2.0 Hz, 2H), 7.73 (d, J=9.0Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 157.7, 155.2 (quint, J_(CF)=19.0Hz), 133.3, 126.5 (quint, J_(CF)=4.0 Hz), 122.7, 85.9, 81.7; ¹⁹F NMR(376 MHz, CDCl₃) δ 82.6 (quint, J=150.5 Hz, 1 F), 62.3 (d, J=150.3 Hz, 4F); HRMS (ESI) m/z calcd for C₉H₄O₂F₅S ([M−H]⁻) 270.9858, found270.9858.

Trimethyl((3-(pentafluoro-λ6-sulfaneyl)phenyl)ethynyl)silane. A solutionof Pd(PPh₃)₂Cl₂ (0.0365 g, 0.0519 mmol), CuI (0.0100 g, 0.0519 mmol),and (3-bromophenyl)pentafluoro-6-sulfane (1.50 g, 5.19 mmol) in Et₃N (11mL) was sparged with Ar for 10 min, treated with(trimethylsilyl)acetylene (1.10 mL, 7.79 mmol), sparged with Ar for 5min heated to 80° C. for 22 h, cooled to rt, filtered through Celite,washed (Et₂O) until the washes appeared colorless. The combinedfiltrates were concentrated under reduced pressure. The crude residuewas purified by chromatography on SiO₂ (hexanes) to givetrimethyl((3-(pentafluoro-λ6-sulfaneyl)phenyl)ethynyl)silane (1.29 g,4.29 mmol, 83%) as a yellow oil: IR (CH₂Cl₂) 2963, 2902, 2168, 1601,1479, 1421, 1251, 1109, 831, 803, 789, 759, 683 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 7.87 (t, J=2.0 Hz, 1H), 7.68 (ddd, J=8.0, 2.0, 0.8 Hz, 1H),7.58 (d, J=8.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 0.29 (s, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 153.7 (quint, J_(CF)=17.8 Hz), 134.8, 129.5 (quint,J_(CF)=4.6 Hz), 128.6, 125.8 (quint, J_(CF)=4.8 Hz), 124.4, 102.8, 96.7,−0.3; ¹⁹F NMR (376 MHz, CDCl₃) δ 83.6 (quint, J=150.4 Hz, 1 F), 62.5 (d,J=150.3 Hz, 4 F); HRMS (ESI) m/z calcd for C₁₁H₁₃F₅SiS ([M]⁺) 300.0427,found 300.0405.

3-(3-(Pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid. A solution of CsF(0.783 g, 5.15 mmol) in dry DMSO (3 mL) under CO₂ (balloon) at rt wastreated a solution oftrimethyl((3-(pentafluoro-λ6-sulfaneyl)phenyl)ethynyl)silane (1.29 g,4.30 mmol) in DMSO (5.6 mL) dropwise and the reaction was stirred underCO₂ at rt overnight. The reaction mixture was diluted with H₂O (90 mL)and extracted with CH₂Cl₂ (2×50 mL). The aqueous layer was acidified(>pH 1) with 6M aqueous HCl at 0° C. and then extracted with Et₂O (3×50mL). The combined organic layers were washed with H₂O (50 mL), dried(MgSO₄), concentrated under reduced pressure, and further dried underhigh vacuum to give 3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid(0.935 g, 3.43 mmol, 80%) as tan solid: Mp 121.1-124.4° C.; IR (CDCl₃)2831, 2218, 1688, 1479, 1426, 1214, 831, 791, 768, 680 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 10.92 (s, 1H), 8.01 (t, J=2.0 Hz, 1H), 7.87 (ddd, J=8.0,2.0, 0.9 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H); ¹³CNMR (100 MHz, CDCl₃) δ 158.1, 153.8 (quint, J_(CF)=19.0 Hz), 135.9,130.7 (quint, J_(CF)=5.0 Hz), 129.3, 128.4 (quint, J_(CF)=4.0 Hz),120.2, 86.2, 81.0; ¹⁹F NMR (376 MHz, CDCl₃) δ 82.5 (quint, J=150.4 Hz, 1F), 62.5 (d, J=150.4 Hz, 4 F); HRMS (ESI) m/z calcd for C₉H₄O₂F₅S([M−H]⁻) 270.9858, found 270.9856.

3-(5-Methylthiophen-2-yl)propiolic acid (He et al., Chem. Sci. 2013,4:3478-3483; Paegle et al., Euro. J. Org. Chem. 2015; 2015:4389-4399;Kub et al., Macromolecules 2010, 34:2124-2129). A solution ofPd(PPh₃)₂Cl₂ (0.0269 g, 0.0877 mmol), CuI (0.0167 g, 0.0877 mmol), and2-bromo-5-methyl thiophene (1.00 mL, 8.77 mmol) in Et₃N (17.5 mL)sparged with Ar for 15 min and treated with (trimethylsilyl)acetylene(1.9 mL, 13.2 mmol) and the mixture was further sparged for 2 min,heated to 80° C. overnight, cooled to rt, filtered through Celite,washed (Et₂O) until the washes appeared colorless and the filtrate wasconcentrated under reduced pressure. The crude residue was purified bychromatography on SiO₂ (hexanes) to give thetrimethyl((5-methylthiophen-2-yl)ethynyl)silane 1.06 g, 5.47 mmol, 62%)as a pale yellow oil.

To a solution of CsF (0.994 g, 6.54 mmol) in dry DMSO (8 mL) under anatmosphere of CO₂ (balloon) at rt was added a solution oftrimethyl((5-methylthiophen-2-yl)ethynyl)silane (1.06 g, 5.45 mmol)dropwise and the reaction was stirred under CO₂ at rt overnight. Thereaction mixture was diluted with H₂O (100 mL) and extracted with CH₂Cl₂(2×25 mL). The aqueous layer was acidified (>pH 1) with 6 M aqueous HClat 0° C. and extracted with Et₂O (3×25 mL). The combined organic layerswere washed with brine (50 mL), dried (MgSO₄), filtered, andconcentrated under reduced pressure to give the product (0.571 g, 3.44mmol, 63%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 10.14 (bs, 1H),7.36 (d, J=3.3 Hz, 1H), 6.73 (dd, J=3.3 Hz, 1H), 2.52 (s, 3H).

3-(3,5-Bis(trifluoromethyl)phenyl)propiolic acid. A solution ofPd(PPh₃)₂Cl₂ (0.239 g, 0.341 mmol), CuI (0.0650 g, 0.341 mmol), and1-bromo-3,5-bis(trifluoromethyl)benzene (2.00 g, 6.83 mmol) in Et₃N (13mL) was sparged with Ar for 10 min and treated with(trimethylsilyl)acetylene (1.42 mL, 10.2 mmol) and the solution wassparged with Ar for 2 min. The resulting mixture was heated to 80° C.for 22 h, cooled to rt, and filtered through Celite, which was washedwith Et₂O until the washes appeared colorless. The filtrate wasconcentrated under reduced pressure and the crude residue was purifiedby chromatography on SiO₂ (hexanes) to give the desired product (1.79 g,5.78 mmol) as a light yellow solid.

A solution of CsF (1.05 g, 6.92 mmol) in DMSO (4.6 mL) under CO₂ at rtwas treated with a solution of((3,5-bis(trifluoromethyl)phenyl)ethynyl)trimethylsilane (1.79 g, 5.77mmol) in DMSO (7 mL) dropwise and the reaction was stirred under CO₂ atrt overnight. The reaction mixture was diluted with H₂O (90 mL) andextracted with CH₂Cl₂ (2×50 mL). The aqueous layer was acidified (>pH 1)with 6 M aqueous HCl at 0° C. and then extracted with Et₂O (3×100 mL).The combined organic layers were washed with H₂O (50 mL), dried (MgSO₄).The solvent was concentrated under reduced pressure and further driedunder high vacuum to give 3-(3,5-bis(trifluoromethyl)phenyl)propiolicacid (0.859 g, 3.04 mmol, 45% (2 steps)) as brown solid: Mp 124.5-128.2°C.; IR (CH₂Cl₂) 2915, 2226, 1688, 1377, 1278, 1131, 972, 903, 683 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 11.25 (s, 1H), 8.06 (s, 2H), 7.98 (s, 1H); ¹³CNMR (100 MHz, CDCl₃) δ 157.7, 132.9 (q, J_(CF)=3.4 Hz), 132.6 (q,J_(CF)=34.4 Hz), 124.5 (q, J_(CF)=3.5 Hz), 122.5 (q, J_(CF)=273.2 Hz),121.5, 84.5, 82.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −63.3 (s, 6 F); HRMS (ESI)m/z calcd for C₁₁H₃F₆O₂ ([M−H]⁻) 281.0043, found 281.0039

3-(4-Chloro-2-fluorophenyl)propiolic acid. A solution of Pd(PPh3)₂Cl₂(0.197 g, 0.281 mmol), CuI (0.0535 g, 0.281 mmol), and4-chloro-2-fluoro-1-iodobenzene (1.80 g, 7.02 mmol) in Et₃N (14 mL) wassparged with Ar for 10 min followed by addition of(trimethylsilyl)acetylene (1.46 mL, 10.5 mmol) and the solution wasfurther sparged with Ar for 2 min. The resulting mixture was heated to80° C. for 22 h. After cooling the reaction to rt, the solution wasfiltered through Celite, which was washed with Et₂O until the washesappeared colorless. The filtrate was concentrated under reducedpressure. The crude residue was purified by chromatography on SiO₂(hexanes) to give ((4-chloro-2-fluorophenyl)ethynyl)trimethylsilane(1.42 g, 6.26 mmol) as a yellow oil.

A solution of CsF (1.14 g, 7.51 mmol) in DMSO (5 mL) under CO₂ at rt wastreated with a solution of((4-chloro-2-fluorophenyl)ethynyl)trimethylsilane (1.42 g, 6.26 mmol) inDMSO (7 mL) dropwise and the reaction was stirred under CO₂ at rtovernight. The reaction mixture was diluted with H₂O (90 mL) andextracted with CH₂Cl₂ (2×50 mL). The aqueous layer was acidified (>pH 1)with 6 M aqueous HCl at 0° C. and then extracted with Et₂O (3×100 mL).The combined organic layers were washed with H₂O (50 mL), dried (MgSO₄),concentrated under reduced pressure, and dried under high vacuum to give3-(4-chloro-2-fluorophenyl)propiolic acid (0.828 g, 4.17 mmol, 60% (2steps)) as tan solid: Mp 174.1-176.4° C.; IR (CH₂Cl₂) 2972, 2233, 1720,1603, 1486, 1387, 1298, 1189, 1072, 883, 827 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 9.09 (s, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H);¹³C NMR (100 MHz, CDCl₃) δ 163.6 (d, J_(CF)=259.9 Hz), 156.9, 138.7 (d,J_(CF)=10.0 Hz), 135.2 (d, J_(CF)=0.9 Hz), 125.1 (d, J_(CF)=3.7 Hz),117.0 (d, J_(CF)=23.6 Hz), 106.8 (d, J_(CF)=15.5 Hz), 85.1, 81.1; ¹⁹FNMR (376 MHz, CDCl₃) δ −104.3 (s, 1 F); HRMS (ESI) m/z calcd forC₉H₃ClFO₂ ([M−H]⁻) 196.9811, found 196.9831.

Methyl 3-(6-(trifluoromethyl)pyridin-3-yl)propiolate. To two flasks eachcontaining a solution of Pd(PPh₃)₂Cl₂ (0.0466 g, 0.0664 mmol), CuI(0.0126 g, 0.0664 mmol), and 5-bromo-2-trifluoromethyl pyridine (1.50 g,6.64 mmol) in Et₃N (13 mL) sparged with Ar for 10 min followed byaddition of (trimethylsilyl)acetylene (1.4 mL, 9.96 mmol) and spargedwith Ar for 2 min. The resulting mixtures were heated to 80° C.overnight where by TLC (hexanes/EtOAc, 4:1) the SM had been consumed.After cooling the reaction to rt, the reactions were combined, thesolution was filtered through Celite, which was washed with Et₂O (100mL) until the washes appeared colorless. The filtrate was concentratedunder reduced pressure. The crude residue was purified by chromatographyon SiO₂(hexanes/EtOAc, 9:1) to give2-(trifluoromethyl)-5-((trimethylsilyl)ethynyl)pyridine (3.37 g, 13.9mmol) as orange/brown waxy solid that was taken on to the carboxylation.

A solution of CsF (2.52 g, 16.6 mmol) in DMSO (20 mL) under CO₂ at rtwas treated with a solution of2-(trifluoromethyl)-5-((trimethylsilyl)ethynyl)pyridine (3.37 g, 13.9mmol) in DMSO (7 mL) dropwise and the reaction was stirred under CO₂(balloon) at rt for 5 h, treated with MeI (0.95 mL, 15.2 mmol) was addedand the solution was stirred for 1 h at rt. The reaction mixture wasdiluted with H₂O (200 mL), brine (100 mL) and extracted with Et₂O (3×150mL). The combined organic layers were washed with H₂O (100 mL), dried(MgSO₄), and concentrated under reduced pressure. The crude product waspurified by chromatography on SiO₂ (hexanes/EtOAc, 4:1) to give methyl3-(6-(trifluoromethyl)pyridin-3-yl)propiolate (1.87 g, 8.17 mmol, 59% (2steps)) as tan solid: Mp 98.2-99.7° C.; IR (neat) 2962, 2233, 1712,1433, 1337, 1242, 1127, 1085, 864, 745 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.87 (s, 1H), 8.04 (ddd, J=8.0, 1.2, 0.6 Hz, 1H), 7.71 (d, J=8.0 Hz,1H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.4, 153.1, 148.6 (q,J_(CF)=35.5 Hz), 141.2, 121.0 (q, J_(CF)=274.4 Hz), 120.1 (q, J_(CF)=2.8Hz), 120.0, 84.7, 80.7, 53.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −68.3 (s, 3 F);HRMS (ESI) m/z calcd for C₁₀H₇F₃NO₂ ([M+H]⁺) 230.0423, found 230.0422.

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-fluorophenyl)cyclopropyl)-methanone.A solution of 3-(4-fluorophenyl)propiolic acid (0.0800 g, 0.487 mmol)and 1-(5-chloro-2-(trifluoromethyl)phenyl)piperazinehydrochloride (0.142g, 0.536 mmol) in CH₂Cl₂ (4.9 mL) at 0° C. was treated Et₃N (0.27 mL,1.95 mmol). The cooled solution was treated with T3P (50% solution inEtOAc) (0.52 mL, 0.73 mmol) dropwise and the reaction was stirred at 0°C. for 30 min, warmed to rt overnight, diluted with CH₂Cl₂ (30 mL),washed with H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The crude materialwas purified by automated chromatography on SiO₂ (4 g column, liquidload CH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes), to give1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(0.140 g, 0.341 mmol) as a colorless solid.

A solution of1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(0.140 g, 0.341 mmol) in EtOAc (3.4 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0363 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 2 d. TLC (hexanes/EtOAc, 2:1) indicatedthat the SM had been mostly consumed. The reaction was filtered throughCelite (eluting with EtOAc (10 mL)) and the combined filtrates wereconcentrated under reduced pressure. The crude residue was purified byautomated chromatography on SiO₂ (4 g column, 100% hexanes to 40%EtOAc/hexanes, product eluted at 20% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one(0.0510 g, 0.124 mmol) as a colorless solid.

A solution of CrCl₂ (0.0911 g, 0.741 mmol) and(Z)-1-(4-(5-chloro-2-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one(0.0510 g, 0.124 mmol) in dry degassed THF (1.2 mL) was sparged with Arfor 5 min and treated with CH₂ICl (0.071 mL, 0.618 mmol) at rt, stirredfor 2 d at 80° C., cooled to rt, diluted with EtOAc (50 mL) and washedwith 1 M aqueous HCl (3×20 mL). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure. The crude residue waspurified by automated chromatography on SiO₂ (4 g column, liquid loadCH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes, product eluted at 20%EtOAc/hexanes), filtered through basic Al₂O₃ (CH₂Cl₂/EtOAc, 1:1) andconcentrated under reduced pressure. The resulting oil wasrecrystallized from a mixture of hexanes/cyclohexane (1:1), the crystalswere washed with hexanes and dried under high vacuum to give(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-fluorophenyl)cyclopropyl)-methanone.(0.0238 g, 0.0558 mmol, 11% (3 steps) (100% purity by ELSD)) as acolorless solid: Mp 101.0-103.2° C.; IR (CH₂Cl₂) 2917, 1639, 1513, 1418,1308, 1225, 1126, 1085, 1031, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.45(dd, J=8.4, 0.6 Hz, 1H), 7.25-7.22 (m, 1H), 7.16-7.11 (m, 2H), 7.00 (d,J=1.8 Hz, 1H), 6.99-6.93 (m, 2H), 3.92-3.86 (m, 1H), 3.79-3.73 (m, 1H),3.67 (ddd, J=12.6, 8.6, 3.2 Hz, 1H), 3.37 (ddd, J=12.6, 9.0, 3.2 Hz,1H), 3.01-2.95 (m, 2H), 2.49-2.39 (m, 2H), 2.31-2.25 (m, 1H), 2.19 (ddd,J=9.0, 8.6, 5.8 Hz, 1H), 1.83 (dt, J=6.8, 5.8 Hz, 1H), 1.36 (td, J=8.6,5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 161.6 (d, J_(CF)=245.1Hz), 149.1, 132.5, 131.1, 130.1 (q, J_(CF)=32.7 Hz), 129.1, 129.0, 123.6(q, J_(CF)=272.2 Hz), 120.8 (q, J_(CF)=3.8 Hz), 117.2 (q, J_(CF)=3.8Hz), 115.0 (d, J_(CF)=21.3 Hz), 51.3, 51.0, 45.3, 41.9, 23.9, 23.5 10.7;¹⁹F NMR (376 MHz, CDCl₃) δ −62.6 (s, 3 F), −116.4 (s, 1 F); HRMS (ESI)m/z calcd for C₂₁H₂₀ClF₄N₂O ([M+H]⁺) 427.1195, found 427.1192.

3-(4-Fluorophenyl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one.A solution of 3-(4-fluorolphenyl)propionic acid (0.150 g, 0.914 mmol)and 2-(1-piperazinyl)pyrimidine (0.188 g, 0.841 mmol) in CH₂Cl₂ (9.1 mL)at 0° C. was treated Et₃N (0.51 mL, 3.66 mmol). The cooled solution wastreated with T3P (50% solution in EtOAc) (1.0 mL, 1.37 mmol) dropwiseand the reaction was stirred at 0° C. for 30 min and allowed to warm tort overnight. The reaction was diluted with CH₂Cl₂ (30 mL) and washedwith H₂O (20 mL), dried (MgSO₄), filtered, and concentrated underreduced pressure. The crude material was purified by automatedchromatography on SiO₂ (4 g column, gradient hexanes to EtOAc), to give3-(4-fluorophenyl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one(0.223 g, 0.719 mmol, 79%) as a colorless solid: Mp 168.4-170.8° C.; IR(CH₂Cl₂) 2859, 2217, 1618, 1585, 1506, 1435, 1355, 1261, 1227, 980, 838,732 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=4.6 Hz, 2H), 7.56 (dd,J=8.8, 5.3 Hz, 2H), 7.08 (t, J=8.8 Hz, 2H), 6.56 (t, J=4.6 Hz, 1H),3.95-3.93 (m, 2H), 3.88 (app dd, J=6.6, 3.4 Hz, 4H), 3.76 (app dd,J=6.6, 4.1 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 163.6 (d, J=253.0 Hz),161.4, 157.8, 153.1, 134.6 (d, J=8.7 Hz), 116.4 (d, J=3.6 Hz), 116.1 (d,J=22.1 Hz), 110.6, 90.0, 80.8, 46.8, 44.0, 43.3 41.5.; ¹⁹F NMR (376 MHz,CDCl₃) δ −107.3 (s, 1 F); HRMS (ESI) m/z calcd for C₁₇H₁₆FN₄O ([M+H]⁺)311.1303, found 311.1301.

((1RS,2SR)-2-(4-Fluorophenyl)cyclopropyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone.A solution of3-(4-fluorophenyl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)prop-2-yn-1-one(0.200 g, 0.644 mmol) in EtOAc (6.4 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0685 g, equivalent to 5 mol %Pd). The reaction vessel was placed under vacuum and backfilled with H₂(balloon, 4×) and stirred for 18 h at rt, filtered through Celite,washed (EtOAc), and the combined filtrates were concentrated underreduced pressure. The crude residue was purified by automatedchromatography on SiO₂ (4 g column, hexanes to 60:40 hexanes:EtOAc) togive(Z)-3-(4-fluorophenyl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one(0.211 g, 0.676 mmol) as a colorless solid that was taken on to thecyclopropanation.

A solution of CrCl₂ (0.472 g, 3.84 mmol) and(Z)-3-(4-fluorophenyl)-1-(4-(pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one(0.200 g, 0.640 mmol) in dry degassed THF (6.4 mL) (previously spargedwith Ar for 15 min) was treated with CH₂ICl (0.37 mL, 3.20 mmol) andfurther sparged with Ar for 2 min. The reaction mixture was stirred for20 h at 80° C., cooled to rt, diluted with EtOAc (10 mL), filteredthrough a plug of basic Al₂O₃ (EtOAc), and concentrated under reducedpressure. The crude material was purified by automated chromatography onSiO₂ (4 g column, hexanes to 60% EtOAc:hexanes) to give((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone(0.128 g, 0.392 mmol, 61% (2 steps) (100% purity by ELSD)) as acolorless solid: Mp 141.9-145.3° C.; IR (CH₂Cl₂) 2922, 1636, 1583, 1510,1432, 1359, 1224, 1027, 981, 837, 797 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ8.28 (d, J=4.6 Hz, 2H), 7.12 (dd, J=8.7, 5.3 Hz, 2H), 6.92 (t, J=8.7 Hz,2H), 6.50 (t, J=4.6 Hz, 1H), 4.00 (dt, J=13.3, 4.4 Hz, 1H), 3.93 (dt,J=13.0, 4.4 Hz, 1H), 3.76 (ddd, J=13.0, 5.1, 3.6 Hz, 1H), 3.66 (dt,J=13.0, 4.4 Hz, 1H), 3.53 (ddd, J=13.0, 8.8, 3.6 Hz, 1H), 3.26 (ddd,J=13.0, 8.8, 3.4 Hz, 1H), 3.13 (ddd, J=13.0, 8.8, 3.6 Hz, 1H), 3.00(ddd, J=13.0, 8.8, 3.6 Hz, 1H), 2.49-2.43 (m, 1H), 2.18 (ddd, J=9.2,8.4, 5.8 Hz, 1H), 1.83 (q, J=5.8 Hz, 1H), 1.34 (td, J=8.4, 5.8 Hz, 1H);¹³C NMR (100 MHz, CDCl₃) δ 167.3, 161.7 (d, J_(CF)=244.9 Hz), 161.3,157.7, 133.0, 129.0 (d, J_(CF)=8.0 Hz), 115.0 (d, J_(CF)=21.3 Hz),110.3, 45.0, 43.8, 43.4, 41.6, 23.9, 23.5, 10.6; ¹⁹F NMR (470 MHz,CDCl₃) δ −116.4 (s, 1 F); HRMS (ESI) m/z calcd for C₁₈H₂₀FN₄O ([M+H]⁺)327.1616, found 327.1616.

Racemic((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%Methanol/CO₂, 7 mL/min, 100 bar, 90 μL injection, 20 mg/mL in MeOH) togive((1S,2R)-2-(4-fluorophenyl)cyclopropyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone(retention time 7.63 min) as a colorless solid (100% purity by ELSD):[α]¹⁷D−207.0 (c 0.53, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.28 (d, J=4.6Hz, 1H), 7.12 (dd, J=8.6, 5.3 Hz, 1H), 6.92 (t, J=8.6 Hz, 1H), 6.50 (t,J=4.6 Hz, 1H), 4.02-3.91 (m, 2H), 3.79-3.73 (m, 1H), 3.69-3.64 (m, 1H),3.56-3.48 (m, 2H), 3.29-3.21 (m, 1H), 3.16-3.08 (m, 1H), 2.98 (ddd,J=12.6, 9.0, 3.7 Hz, 1H), 2.51-2.42 (m, 1H), 2.18 (ddd, J=9.0, 8.4, 6.0,1H), 1.83 (q, J=5.6 Hz, 1H), 1.35 (td, J=8.4, 5.6 Hz, 1H). Theenantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10 mm); 30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm; retention time: 8.0 min).

((1R,2S)-2-(4-Fluorophenyl)cyclopropyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methanone(retention time 8.61 min) was obtained as a colorless solid (100% purityby ELSD): [α]¹⁷ _(D)+213.2 (c 0.54, MeOH); NMR (300 MHz, CDCl₃) δ 8.28(d, J=4.6 Hz, 2H), 7.12 (dd, J=8.6, 5.3 Hz, 2H), 6.92 (t, J=8.6 Hz, 2H),6.50 (t, J=4.6 Hz, 1H), 4.02-3.90 (m, 2H), 3.79-3.73 (m, 1H), 3.69-3.62(m, 1H), 3.57-3.48 (m, 2H), 3.30-3.21 (m, 1H), 3.16-3.08 (m, 1H), 2.98(ddd, J=13.0, 9.0, 3.5 Hz, 1H), 2.47 (td, J=9.0, 6.0 Hz, 1H), 2.18 (ddd,J=9.0, 8.4, 6.0 Hz, 1H), 1.83 (q, J=5.6 Hz, 1H), 1.35 (td, J=8.4, 5.6Hz, 1H). The enantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10mm); 30% Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm; retention time: 9.0min).

(Z)-1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one-2,3-d2.A solution of1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(0.150 g, 0.140 mmol) in anhydrous EtOAc (4.2 mL) was treated withLindlar's catalyst (5% Pd on CaCO₃, lead poisoned, 0.0447 g, 0.0210mmol, equivalent to 5 mol % Pd). The reaction was placed under a balloonof D₂ (3 vacuum/backfill cycles) and stirred vigorously at rt for 24 h,filtered through Celite, washed (EtOAc), and concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load with CH₂Cl₂, hexanes to 30% EtOAc:hexanes,product eluted at 25% EtOAc:hexanes) to give(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one-2,3-d2(0.0919 g, 0.255 mmol, 61%, 97% deuterium incorporation) as a colorlesssolid: Mp 122.1-124.8° C.; IR (CH₂Cl₂) 2918, 2819, 1628, 1595, 1505,1432, 1222, 1022, 852, 817, 735 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.39(dd, J=8.6, 5.4 Hz, 2H), 7.07-7.01 (m, 3H), 6.95 (dd, J=8.2, 2.0 Hz,1H), 6.79 (d, J=2.0 Hz, 1H), 3.79 (bs, 2H), 3.48 (t, J=5.0 Hz, 2H), 2.80(t, J=5.0 Hz, 2H), 2.52 (t, J=5.0 Hz, 2H), 2.20 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 167.2, 162.6 (d, J=249.3 Hz), 151.7, 132.1 (t, J_(CD)=23.6Hz), 132.0, 131.7, 131.4 (d, J_(CF)=3.2 Hz), 130.8, 130.2 (d, J_(CF)=8.1Hz), 123.6, 122.2 (t, J_(CD)=24.2 Hz), 119.5, 115.6 (d, J_(CF)=21.4 Hz),51.4, 51.1, 46.5, 41.4 17.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −112.0 (s, 1 F);HRMS (ESI) m/z calcd for C₂₀H₁₉D₂ClFN₂O ([M+H]⁺) 361.1446, found361.1446

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl-1,2-d2)methanone.A solution of CrCl₂ (0.225 g, 1.83 mmol) and(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(2-(4-fluorophenyl)cyclopropyl-1,2-d2)methadone(0.110 g, 0.305 mmol) in dry degassed THF (3 mL) (previously spargedwith Ar for 15 min) was treated with CH₂ICl (0.18 mL, 1.52 mmol) andsparged with Ar for 2 min. The reaction mixture was stirred for 24 h at80° C., cooled to rt, diluted with EtOAc (50 mL), and washed with 1 MHCl (3×20 mL). The organic layer was dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude residue was purified byautomated chromatography on SiO₂ (4 g column, liquid load CH₂Cl₂,hexanes to 40% EtOAc/hexanes) to give a yellow oil that was filteredthrough basic Al₂O₃ (1:1 CH₂Cl₂/EtOAc) concentrated under reducedpressure to a clear oil that was triturated in minimal cyclohexane togive a colorless solid that was dried under high vacuum to give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl-1,2-d2)methanone(0.0799 g, 0.213 mmol, 70% (100% purity by ELSD)) as a colorless solid:Mp 100.2-102.7° C.; IR (CH₂Cl₂) 2917, 1632, 1512, 1431, 1221, 1032, 818,729 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.16-7.11 (m, 2H), 7.06 (d, J=8.2Hz, 1H), 7.00-6.94 (m, 3H), 6.71 (d, J=2.0 Hz, 1H), 3.81-3.77 (m, 1H),3.72-3.59 (m, 2H), 3.37-3.31 (m, 1H), 2.79-2.69 (m, 2H), 2.33-2.28 (m,1H), 2.24-2.20 (m, 4H), 1.81 (d, J=5.4 Hz, 1H), 1.32 (d, J=5.4 Hz, 1H);¹³C NMR (100 MHz, CDCl₃) δ 167.2, 161.5 (d, J_(CF)=244.7 Hz), 151.8,133.0 (d, J_(CF)=3.1 Hz), 131.9, 131.7, 130.9, 129.0 (d, J_(CF)=7.7 Hz),123.5, 119.6, 114.9 (d, J_(CF)=21.3 Hz), 51.7, 51.5, 45.5, 42.1, 23.4(t, J_(CD)=25.4 Hz), 23.0 (t, J_(CD)=24.6 Hz) 17.3, 10.4; ¹⁹F NMR (376MHz, CDCl₃) δ −116.3 (s, 1 F); HRMS (ESI) m/z calcd for C₂₁H₂₁D₂ClFN₂O([M+H]⁺) 375.1603, found 375.1602.

Racemic(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-fluorophenyl)cyclopropyl-1,2-d2)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm) injection volume 90 μL, 20mg/mL) to give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1S,2R)-2-(4-fluorophenyl)cyclopropyl-1,2-d2)methanone(retention time 7.58 min) as a colorless viscous oil (100% purity byELSD): [α]¹⁸ _(D)−152.0 (c 0.70, MeOH); ¹H NMR (300 MHz, CDCl₃) δ7.16-7.12 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 7.01-6.94 (m, 3H), 6.72 (d,J=1.8 Hz, 1H), 3.82-3.76 (m, 1H), 3.74-3.58 (m, 2H), 3.39-3.31 (m, 1H),2.80-2.69 (m, 2H), 2.80-2.69 (m, 2H), 2.35-2.17 (m, 5H), 1.82 (d, J=5.4Hz, 1H), 1.33 (d, J=5.4 Hz, 1H). The enantiomeric excess was >99.9% ee(SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min, p=100 bar,220 nm; retention time: 7.8 min).

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1R,2S)-2-(4-fluorophenyl)cyclopropyl-1,2-d2)methanone(retention time 9.28 min) was obtained as a colorless viscous oil (100%purity by ELSD): [α]¹⁹ _(D)+154.0 (c 0.66, MeOH); ¹H NMR (300 MHz,CDCl₃) δ 7.17-7.10 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 7.02-6.94 (m, 3H),6.72 (d, J=2.0 Hz, 1H), 3.83-3.74 (m, 1H), 3.73-3.58 (m, 2H), 3.39-3.31(m, 1H), 2.80-2.69 (m, 2H), 2.36-2.18 (m, 5H), 1.82 (d, J=5.4 Hz, 1H),1.33 (d, J=5.4 Hz, 1H). The enantiomeric excess was >99.9% ee (SFCChiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm;retention time: 9.6 min).

1-(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one.A solution of 3-(4-(trifluoromethyl)phenyl)propiolic acid (0.100 g,0.467 mmol) and1-(5-chloro-2-(trifluoromethyl)phenyl)piperazinehydrochloride (0.155 g,0.514 mmol) in CH₂Cl₂ (4.7 mL) cooled to 0° C. was treated with Et₃N(0.26 mL, 1.87 mmol). The cooled solution was treated with T3P (50 wt. %solution in EtOAc, 0.49 mL, 0.701 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min and allowed to warm to rt overnight, dilutedwith CH₂Cl₂ (30 mL) and washed with H₂O (20 mL), satd. aqueous NaHCO₃(20 mL), dried (MgSO₄), filtered, and concentrated under reducedpressure. The crude material was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, hexanes to 30% EtOAc/hexanes), togive1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.161 g, 0.350 mmol, 75%) as a colorless solid: Mp 145.8-148.8° C.; IR(CH₂Cl₂) 2928, 2827, 2223, 1634, 1596, 1432, 1322, 1310, 1122, 1107,1033, 844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.65 (app q, J=7.3 Hz, 4H),7.58 (d, J=8.4 Hz, 1H), 7.28-7.24 (m, 2H), 3.96 (app t, J=5.0 Hz, 2H),3.84 (app t, J=5.0 Hz, 2H), 3.00 (app t, J=5.0 Hz, 2H), 2.94 (app t,J=5.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 152.5, 138.8, 132.5, 131.6 (q,J_(CF)=33.0 Hz), 128.5 (q, J_(CF)=5.4 Hz), 125.7 (q, J_(CF)=29.4 Hz),125.7, 125.4 (q, J_(CF)=3.7 Hz), 124.7, 124.1, 123.5 (q, J_(CF)=270.8Hz, 2 C), 89.0, 82.7, 53.6, 52.7, 47.3, 41.8; ¹⁹F NMR (376 MHz, CDCl₃) δ−60.3 (s, 3 F), −63.1 (s, 3 F); HRMS (ESI) m/z calcd for C₂₁H₁₆ClF₆N₂O([M+H]⁺) 461.0850, found 461.0847.

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone.A solution of1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.127 g, 0.276 mmol) in EtOAc (2.8 mL) was treated with quinoline (0.16mL, 1.38 mmol) and 5% Pd/BaSO₄ (0.0059 g, equivalent to 1 mol % Pd). Thereaction was placed under and atmosphere of H₂ (balloon) (3vacuum/backfill cycles) and stirred at rt for 1.5 h, filtered throughCelite, washed (EtOAc), and the combined filtrates were washed with 1 Maqueous HCl (10 mL), dried (MgSO₄), filtered, and concentrated underreduced pressure. The crude residue was purified by automatedchromatography on SiO₂ (4 g column, liquid load CH₂Cl₂, hexanes to 30%EtOAc/hexanes; product eluted at 20% EtOAc) to give the product (0.114g, 0.246 mmol) as a colorless solid.

To a flame dried 5 mL microwave vial containing anhydrous CrCl₂ (0.182g, 0.148 mmol) was added a solution of(Z)-1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)-phenyl)prop-2-en-1-one(0.114 g, 0.246 mmol) in anhydrous THF (2.5 mL) and the mixture wassparged with Ar for 15 min and added CH₂ICl (0.14 mL, 1.23 mmol) at rtand under Ar atmosphere. The reaction mixture was stirred for 2 d at 80°C. The reaction was cooled to rt, combined, quenched by the addition ofEtOAc (50 mL) and washed with 1 M aqueous HCl (3×20 mL). The organiclayer was dried (MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes,product eluted at 20% EtOAc/hexanes) to give a clear oil that wasfiltered through basic Al₂O₃ (1:1 CH₂Cl₂/EtOAc) concentrated, and driedunder high vacuum to give(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0681 g, 0.143 mmol, 52% (2 steps) (100% purity by ELSD)) as acolorless solid: Mp 138.0-139.9° C.; IR (CH₂Cl₂) 3014, 2825, 1641, 1596,1326, 1309, 1116, 1031, 844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d,J=8.2 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.19 (dd,J=8.5, 1.4 Hz, 1H), 6.89 (d, J=1.4 Hz, 1H), 3.95 (bd, J=12.4 Hz, 1H),3.73 (bd, J=12.4 Hz, 1H), 3.54 (bt, J=10.0 Hz, 1H), 3.21 (bt, J=10.0 Hz,1H), 2.74 (bt, J=10.0 Hz, 2H), 2.50 (td, J=8.9, 7.1 Hz, 1H), 2.29-2.19(m, 2H), 1.98 (bt, J=8.9 Hz, 1H), 1.92 (q, J=6.2 Hz, 1H), 1.43 (td,J=8.4, 5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 152.7, 142.1,138.9, 128.8 (q, J_(CF)=32.6 Hz), 128.4 (q, J_(CF)=5.8 Hz), 127.9, 125.7(q, J_(CF)=30.2 Hz), 125.6, 125.0 (q, J_(CF)=3.7 Hz), 124.6 (q,J_(CF)=273.0 Hz), 124.4, 123.6 (q, J_(CF)=272.9 Hz), 53.7, 52.9, 45.5,42.1, 24.7, 23.9, 11.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −60.4 (s, 3 F), −62.2(s, 3 F); HRMS (ESI) m/z calcd for C₂₂H₂₀ClF₆N₂O ([M+H]⁺) 477.1163,found 477.1160.

Racemic(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (25%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm) injection volume 90 μL, 20mg/mL) to give(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(retention time 3.57 min) as a colorless viscous oil (100% purity byELSD): [α]¹⁹ _(D)−106.6 (c 0.68, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 7.57(d, J=8.1 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.20(d, J=8.4 Hz, 1H), 6.88 (d, J=0.9 Hz, 1H), 3.98-3.93 (m, 1H), 3.76-3.70(m, 1H), 3.54 (ddd, J=12.3, 9.3, 3.0 Hz, 2H), 3.21 (ddd, J=12.3, 9.3,3.0 Hz, 2H), 2.76-2.71 (m, 2H), 2.51 (td, J=9.3, 7.2 Hz, 1H), 2.30-2.18(m, 2H), 2.00-1.89 (m, 2H), 1.44 (td, J=8.4, 5.7 Hz, 1H). Theenantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10 mm); 25%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm; retention time: 3.8 min).

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone(retention time 4.20 min) was obtained as a colorless viscous oil (100%purity by ELSD): [α]¹⁹ _(D)+111.1 (c 0.71, MeOH); ¹H NMR (300 MHz,CDCl₃) δ 7.57 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 3.99-3.93 (m, 1H),3.76-3.70 (m, 1H), 3.58-3.49 (m, 1H), 3.25-3.16 (m, 1H), 2.76-2.71 (m,2H), 2.51 (q, J=9.6 Hz, 1H), 2.30-2.18 (m, 2H), 2.00-1.89 (m, 2H), 1.44(td, J=8.4, 5.6 Hz, 1H). The enantiomeric excess was >99.9% ee (SFCChiralpak-IC (250×10 mm); 25% Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm;retention time: 4.1 min).

4-Bromo-2-(4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazin-1-yl)benzonitrile.A solution of 3-(4-trifluoromethylphenyl)propiolic acid (0.400 g, 1.87mmol) and 4-bromo-2-(piperazin-1-yl)benzonitrile hydrochloride (0.735 g,2.43 mmol) in CH₂Cl₂ (19 mL) at 0° C. was treated Et₃N (1.0 mL, 7.47mmol). The cooled solution was treated with T3P (50% solution in EtOAc)(2.0 mL, 2.80 mmol) dropwise and the reaction was stirred at 0° C. for30 min, warmed to rt overnight, diluted with EtOAc (80 mL) and washedwith H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried (MgSO₄), filtered,and concentrated under reduced pressure. The crude residue was purifiedby chromatography on SiO₂ (hexanes/EtOAc, 1:1), to give4-bromo-2-(4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazin-1-yl)benzonitrile(0.784 g, 1.70 mmol, 91%) as a pale yellow solid: Mp 176.3-179.1° C.; IR(CH₂Cl₂) 2824, 2222, 1626, 1583, 1432, 1324, 1163, 1129, 1107, 1035,949, 928, 846, 816 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.66 (dd, J=7.8 Hz,4H), 7.45 (d, J=8.0 Hz, 1H), 7.22 (dd, J=8.0, 1.6 Hz, 1H), 7.15 (d,J=1.6 Hz, 1H), 4.05 (t, J=5.0 Hz, 2H), 3.91 (t, J=5.0 Hz, 2H), 3.31 (t,J=5.0 Hz, 2H), 3.22 (t, J=5.0 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 155.6,152.6, 135.1, 132.6, 131.8 (q, J_(CF)=32.8 Hz), 128.8, 125.9, 125.5 (q,J_(CF)=3.8 Hz), 124.0, 123.5 (q, J_(CF)=272.5 Hz), 122.7, 117.4, 105.1,89.3, 82.5, 52.0, 50.7, 47.0, 41.5; ¹⁹F NMR (470 MHz, CDCl₃) δ −63.1 (s,3 F); HRMS (ESI) m/z calcd for C₂₁H₁₆BrF₃N₃O ([M+H]⁺) 462.0423, found462.0423.

4-Bromo-2-(4-((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile.A solution of4-bromo-2-(4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazin-1-yl)benzonitrile(0.750 g, 1.62 mmol) in EtOAc (16 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.691 g, equivalent to 20 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by chromatography on SiO₂(hexanes/EtOAc, 1:4) to give(Z)-4-bromo-2-(4-(3-(4-(trifluoromethyl)phenyl)acryloyl)piperazin-1-yl)benzonitrile(0.318 g, 0.685 mmol) as a tan foam.

A solution of CrCl₂ (0.477 g, 0.899 mmol) and(Z)-4-bromo-2-(4-(3-(4-(trifluoromethyl)phenyl)-acryloyl)piperazin-1-yl)benzonitrile(0.300 g, 0.646 mmol) in dry degassed THF (6.5 mL) was sparged with Arfor 5 min and treated with CH₂ICl (0.37 mL, 3.23 mmol) at rt, stirredfor 2 d at 80° C., cooled to rt, diluted with EtOAc (150 mL) and washedwith 1 M aqueous HCl (3×50 mL). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure. The crude residue waspurified by chromatography on SiO₂ (hexanes/EtOAc, 1:9) to give acolorless oil that was filtered through basic Al₂O₃ (EtOAc) concentratedand further dried under high vacuum to give4-bromo-2-(4-((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile(0.148 g, 0.309 mmol, 20% (2 steps) (100% purity by ELSD)) as acolorless oil: IR (CH₂Cl₂) 2833, 2222, 1642, 1583, 1484, 1436, 1326,1228, 1116, 1069, 844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J=8.5 Hz,2H), 7.38 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.17 (dd, J=8.0,1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 3.93 (dt, J=13.0, 3.5 Hz, 1H), 3.78(dt, J=13.0, 3.5 Hz, 1H), 3.67 (ddd, J=13.0, 9.0, 3.0 Hz, 1H), 3.35(ddd, J=13.0, 9.0, 3.0 Hz, 1H), 3.18-3.15 (m, 1H), 3.08-3.06 (m, 1H),2.55-2.45 (m, 2H), 2.29-2.24 (m, 2H), 1.92 (q, J=6.0 Hz, 1H), 1.43 (td,J=8.0, 6.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 166.8, 155.7, 141.8,135.0, 128.8, 128.8 (q, J_(CF)=32.6 Hz), 127.9, 125.7, 125.1 (q,J_(CF)=3.6 Hz), 124.1 (q, J_(CF)=271.8 Hz), 122.4, 117.5, 105.0, 52.1,50.8, 45.2, 41.7, 24.5, 24.1, 11.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.3 (s,3 F); HRMS (ESI) m/z calcd for C₂₂H₂₀BrF₃N₃O ([M+H]⁺) 478.0736, found478.0734.

Racemic4-bromo-2-(4-((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrilewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (25%Methanol/CO₂, 7 mL/min, 220 nm, p=100 bar, 20 mg/mL in MeOH) to give4-bromo-2-(4-((1S,2R)-2-(4-(trifluoromethyl)-phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile(retention time 10.5 min) as a colorless solid (100% purity by ELSD):[α]¹⁹ _(D)−144.1 (c 1.31, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d,J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.17 (dd,J=8.1, 1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 3.95-3.89 (m, 1H), 3.76-3.67(m, 2H), 3.38-3.33 (m, 1H), 3.16-3.04 (m, 2H), 2.56-2.45 (m, 2H), 2.27(td, J=8.7, 6.0 Hz, 2H), 1.92 (q, J=6.0 Hz, 1H), 1.44 (td, J=8.4, 5.5Hz, 1H). The enantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10mm); 25% MeOH, 7 mL/min, 220 nm, p=100 bar; retention time: 10.8 min).

4-Bromo-2-(4-((1R,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile(retention time 11.6 min) was obtained as a colorless solid (100% purityby ELSD): [α]¹⁹ _(D)+135.8 (c 1.43, MeOH); ¹H NMR (300 MHz, CDCl₃) δ7.52 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.29 (s, 2H), 7.17 (dd,J=8.1, 1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 3.93-3.90 (m, 1H), 3.78-3.67(m, 2H), 3.38-3.33 (m, 1H), 3.17-3.04 (m, 2H), 2.56-2.43 (m, 2H), 2.27(td, J=8.7, 6.0 Hz, 2H), 1.92 (q, J=6.0 Hz, 1H), 1.44 (td, J=8.4, 5.6Hz, 1H). The enantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10mm); 25% MeOH, 7 mL/min, 220 nm, p=100 bar; retention time: 11.8 min).

1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one.A solution of 3-(3-(trifluoromethyl)phenyl)propionic acid (0.0750 g,0.350 mmol) and 1-(5-chloro-2-methylphenyl)piperazine hydrochloride(0.104 g, 0.420 mmol) in CH₂Cl₂ (3.5 mL) cooled to 0° C. was treatedwith Et₃N (0.15 mL, 1.05 mmol). The cooled solution was treated with T3P(50 wt. % solution in EtOAc 0.37 mL, 0.525 mmol) dropwise and thereaction was stirred at 0° C. for 30 min, warmed to rt overnight,diluted with CH₂Cl₂ (30 mL), washed with 1 M aqueous HCl (20 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The crudematerial was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes), to give1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.106 g, 0.261 mmol, 75%) as a colorless solid: Mp 130.3-132.8° C.; IR(CH₂Cl₂) 2820, 2218, 2161, 1631, 1489, 1435, 1201, 1128, 1041, 805, 695cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.74 (d, J=7.8 Hz, 1H),7.68 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H),7.00 (dd, J=8.1, 2.1 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 3.98 (app t, J=5.0Hz, 2H), 3.84 (app t, J=5.0 Hz, 2H), 2.98 (app t, J=5.0 Hz, 2H), 2.90(app t, J=5.0 Hz, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.6,151.6, 135.4, 132.1, 131.8, 131.2 (q, J_(CF)=33.0 Hz), 130.9, 129.17,129.0 (q, J_(CF)=4.1 Hz), 126.6 (q, J_(CF)=3.6 Hz), 123.8, 123.5 (q,J_(CF)=272.5 Hz), 121.4, 119.8, 88.9, 82.1, 51.9, 51.3, 47.4, 41.9; HRMS(ESI) m/z calcd for C₂₁H₁₉ClF₃N₂O ([M+H]⁺) 407.1133, found 407.1130.

(Z)-1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one.To a solution of1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.100 g, 0.246 mmol) in EtOAc (2.5 mL) was added Lindlar's catalyst (5%Pd on CaCO₃, lead poisoned, 0.0105 g, equivalent to 2 mol % Pd) andquinoline (0.015 mL, 0.123 mmol). The reaction vessel was placed undervacuum and backfilled with H₂ (balloon, 4×) stirred for 3.5 h at rt,filtered through Celite, washed (EtOAc), and the combined filtrates werewashed with 1 M aqueous HCl, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude residue was purified by automatedchromatography on SiO₂ (4 g column, liquid load CH₂Cl₂, 10%EtOAc/hexanes to 40% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0932 g, 0.228 mmol, 93%) as a clear colorless solid: Mp 130.3-132.8°C.; IR (CH₂Cl₂) 2918, 1619, 1489, 1440, 1327, 1161, 1096, 1074, 805,737, 696 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.59 (t, J=7.6Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.96 (dd,J=8.1, 2.1 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 6.73 (d, J=12.5 Hz, 1H),6.19 (d, J=12.5 Hz, 1H), 3.80 (app t, J=5.0 Hz, 2H), 3.48 (app t, J=5.0Hz, 2H), 2.80 (app t, J=5.0 Hz, 2H), 2.49 (app t, J=5.0 Hz, 2H), 2.20(s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 151.7, 136.1, 132.0 (2 C),131.8, 131.6, 131.4 (q, J_(CF)=30.4 Hz), 130.9, 129.2, 125.2 (q,J_(CF)=4.0 Hz), 125.0 (q, J_(CF)=3.8 Hz), 124.9, 123.8 (q, J_(CF)=272.3Hz), 123.7, 119.7, 51.4, 51.1, 46.6, 41.5, 17.3; HRMS (ESI) m/z calcdfor C₂₁H₂₁ClF₃N₂O ([M+H]⁺) 409.1289, found 409.1289.

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(3-(trifluoromethyl)phenyl)cyclopropyl)-methanone.A solution of CrCl₂ (0.105 g, 0.851 mmol) and(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0580 g, 0.142 mmol) in dry degassed THF (1.4 mL)(previously spargedwith Ar for 15 min) was treated with CH₂ICl (82 uL, 0.709 mmol) and themixture was sparged with Ar for 2 min, stirred for 20 h at 80° C.,cooled to rt, diluted with Et₂O (50 mL) and washed with 1 M HCl (3×20mL). The organic layer was dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude material was purified by automatedchromatography on SiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to40% EtOAc/hexanes) to give a clear oil that filtered through basic Al₂O₃(CH₂Cl₂/EtOAc, 1:1), recrystallized from hot cyclohexane the motherliquor was decanted and the crystals were washed with hexanes (2×1 mL)and dried under high vacuum to give(4-(5-chloro-2-methylphenyl)-piperazin-1-yl)((1RS,2SR)-2-(3-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0356 g, 0.0842 mmol, 59% (100% purity by ELSD)) as colorless needles:Mp 115.6-117.4° C.; IR (CH₂Cl₂) 2914, 2820, 1639, 1593, 1490, 1437,1225, 1161, 1123, 1074, 806 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.48(m, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0Hz, 1H), 6.95 (dd, J=8.0, 2.1 Hz, 1H), 6.67 (d, J=2.1 Hz, 1H), 3.86 (dt,J=13.0, 2.9 Hz, 1H), 3.74 (dt, J=13.0, 3.2 Hz, 1H), 3.62-3.56 (m, 1H),3.26 (ddd, J=12.4, 9.0, 3.2 Hz, 1H), 2.79-2.70 (m, 2H), 2.53 (td, J=9.0,6.9 Hz, 1H), 2.26 (ddd, J=9.0, 8.4, 5.9 Hz, 1H), 2.20 (s, 3H), 2.10(ddd, J=11.2, 9.0, 2.4 Hz, 1H), 1.91 (app q, J=5.8 Hz, 1H), 1.41 (td,J=8.4, 5.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 151.7, 138.7,131.9, 131.8, 130.9, 130.5, 130.5 (d, J_(CF)=32.2 Hz) 128.7, 125.1 (d,J_(CF)=4.0 Hz), 124.2 (d, J_(CF)=272.2 Hz), 123.6, 123.3 (d, J_(CF)=3.7Hz), 119.6, 51.7, 51.6, 45.5, 42.2, 24.1, 23.9, 17.3, 10.8; ¹⁹F NMR (376MHz, CDCl₃) δ −62.4 (s, 3 F); HRMS (ESI) m/z calcd for C₂₂H₂₃ClF₃N₂O([M+H]⁺) 423.1446, found 423.1443.

Racemic(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(3-(trifluoromethyl)phenyl)-cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm) injection volume 90 μL, 20mg/mL) to give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1S,2R)-2-(3-(trifluoromethyl)phenyl)cyclopropyl)methanone(retention time 4.82 min) as a colorless viscous oil (100% purity byELSD): [α]¹⁹ _(D)−133.5 (c 0.70, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 7.48(bs, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.06 (d, J=8.1Hz, 1H), 6.95 (dd, J=8.1, 2.0 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 3.89-3.82(m, 1H), 3.78-3.71 (m, 1H), 3.63-3.55 (m, 1H), 3.31-3.23 (m, 1H),2.79-2.69 (m, 2H), 2.53 (td, J=8.4, 7.2 Hz, 1H), 2.30-2.07 (m, 6H), 1.92(q, J=5.4 Hz, 1H), 1.41 (td, J=8.4, 5.4 Hz, 1H). The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min,p=100 bar, 220 nm; retention time: 5.0 min).

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1R,2S)-2-(3-(trifluoromethyl)phenyl)cyclopropyl)methanone(retention time 5.57 min) was obtained as a colorless viscous oil (100%purity by ELSD): [α]¹⁹ _(D)+133.1 (c 0.65, MeOH); ¹H NMR (300 MHz,CDCl₃) δ 7.48 (bs, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H),7.06 (d, J=8.0 Hz, 1H), 6.95 (dd, J=8.0, 2.0 Hz, 1H), 6.67 (d, J=2.0 Hz,1H), 3.90-3.82 (m, 1H), 3.78-3.70 (m, 1H), 3.64-3.55 (m, 1H), 3.31-3.23(m, 1H), 2.80-2.69 (m, 2H), 2.53 (td, J=8.4, 6.8 Hz, 1H), 2.30-2.07 (m,6H), 1.92 (q, J=5.4 Hz, 1H), 1.41 (td, J=8.4, 5.4 Hz, 1H). Theenantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10 mm); 30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm; retention time: 5.7 min).

1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one.A solution of 3-(3-(trifluoromethyl)phenyl)propionic acid (0.0763 g,0.356 mmol) and 1-(2-methyl-5-(trifluoromethyl)phenyl)piperazinehydrochloride (0.100 g, 0.356 mmol) in CH₂Cl₂ (3.6 mL) cooled to 0° C.was treated with Et₃N (0.20 mL, 1.42 mmol). The cooled solution wastreated with T3P (50 wt. % solution in EtOAc, 0.38 mL, 0.534 mmol)dropwise and the reaction was stirred at 0° C. for 30 min, warmed to rtovernight, diluted with CH₂Cl₂ (30 mL), washed with 1 M aqueous HCl (20mL), dried (MgSO₄), filtered, and concentrated under reduced pressure.The crude residue was purified by automated chromatography on SiO₂ (4 gcolumn, liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes), to give1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.0819 g, 0.186 mmol, 52%) as a pink solid: Mp 121.8-125.2° C.; IR(CH₂Cl₂) 2924, 2217, 1633, 1436, 1333, 1310, 1166, 1076, 1042, 695 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.67 (d,J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.26 (d,J=8.1 Hz, 1H), 7.22 (s, 1H), 4.00 (app t, J=5.0 Hz, 2H), 3.86 (app t,J=4.8 Hz, 2H), 3.03 (app t, J=5.0 Hz, 2H), 2.93 (app t, J=5.0 Hz, 2H),2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.6, 150.9, 136.8, 135.4,135.4, 131.5, 131.2 (q, J_(CF)=33.0 Hz), 129.2 (s), 129.0 (q,J_(CF)=32.2 Hz), 129.0 (q, J_(CF)=3.9 Hz), 126.6 (q, J_(CF)=3.7 Hz),124.0 (q, J_(CF)=272.0 Hz), 123.4 (q, J_(CF)=272.3 Hz), 121.3, 120.5 (q,J_(CF)=3.8 Hz), 88.9, 82.0, 51.8, 51.3, 47.4, 41.9, 17.9; ¹⁹F NMR (376MHz, CDCl₃) δ −62.3 (s, 3 F), −63.0 (s, 3 F); HRMS (ESI) m/z calcd forC₂₂H₁₉F₆N₂O ([M+H]⁺) 441.1396, found 441.1391.

(Z)-1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one.A solution of1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)-phenyl)prop-2-yn-1-one(0.0800 g, 0.182 mmol) in EtOAc (1.8 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0193 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 2 d, filtered through Celite, washed(EtOAc), and concentrated under reduced pressure. The crude residue waspurified by automated chromatography on SiO₂ (4 g column, liquid loadCH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes, product eluted at 10%EtOAc/hexanes) to give the(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0572 g, 0.129 mmol, 71%) as clear/tan viscous oil: IR (CH₂Cl₂) 2922,1621, 1443, 1418, 1329, 1309, 1163, 1076, 1044, 823 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.68 (s, 1H), 7.59 (t, J=7.7 Hz, 2H), 7.49 (t, J=7.7 Hz,1H), 7.27-7.22 (m, 2H), 7.01 (s, 1H), 6.74 (d, J=12.5 Hz, 1H), 6.20 (d,J=12.5 Hz, 1H), 3.82 (bt, J=4.1 Hz, 2H), 3.50 (app t, J=5.0 Hz, 2H),2.82 (app t, J=5.0 Hz, 2H), 2.47 (app t, J=5.0 Hz, 2H), 2.30 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 166.7, 151.0, 136.8, 136.2, 132.0, 131.6,131.4, 131.2 (q, J_(CF)=32.1 Hz), 129.2, 129.0 (q, J_(CF)=32.3 Hz),125.2 (q, J_(CF)=3.7 Hz), 125.0 (q, J_(CF)=3.8 Hz), 124.9, 124.1 (q,J_(CF)=271.9 Hz), 123.8 (q, J_(CF)=272.5 Hz), 120.4 (q, J_(CF)=3.9 Hz),116.0 (q, J_(CF)=3.7 Hz), 51.3, 51.1, 46.6, 41.5, 17.8; ¹⁹F NMR (376MHz, CDCl₃) δ −62.4 (s, 3 F), −62.7 (s, 3 F); HRMS (ESI) m/z calcd forC₂₂H₂₁F₆N₂O ([M+H]⁺) 443.1553, found 443.1551.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(3-(trifluoromethyl)phenyl)-cyclopropyl)methanone.A solution of CrCl₂ (0.0955 g, 0.777 mmol) and(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0573 g, 0.130 mmol) in dry degassed THF (1.3 mL) was sparged with Arfor 5 min and treated with CH₂ICl (75 uL, 0.648 mmol) at rt and under Aratmosphere, heated for 20 h at 80° C., cooled to rt, diluted with Et₂O(50 mL), and washed with 1 M aqueous HCl (3×20 mL). The organic layerwas dried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude material was purified by automated chromatography on SiO₂ (4 gcolumn, liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes) to give aclear oil that was filtered through basic Al₂O₃ (CH₂Cl₂/EtOAc, 1:1),recrystallized from CH₂Cl₂/hexanes (ca. 1:5) the mother liquor wasdecanted and the clear colorless cubes were washed with hexanes (2×1 mL)and dried under high vacuum to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(3-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0115 g, 0.0252 mmol, 20% (100% purity by ELSD)) as a colorless solid:Mp 113.4-116.8° C.; IR (CH₂Cl₂) 2914, 2824, 1641, 1418, 1328, 1309,1163, 1121, 1073 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.47 (bd, J=7.1 Hz,2H), 7.41 (t, J=7.8 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.24 (s, 2H), 6.92(s, 1H), 3.94 (d, J=12.2 Hz, 1H), 3.79 (d, J=12.2 Hz, 1H), 3.58 (ddd,J=12.2, 9.2, 3.0 Hz, 1H), 3.24 (ddd, J=12.2, 9.2, 2.6 Hz, 1H), 2.77 (td,J=12.2, 3.7 Hz, 2H), 2.53 (td, J=9.2, 7.0 Hz, 1H), 2.29 (s, 3H),2.28-2.18 (m, 2H), 2.11-2.05 (m, 1H), 1.92 (q, J=6.0 Hz, 1H), 1.42 (td,J=8.5, 6.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 151.1, 138.8,136.9, 131.4, 130.6 (q, J_(CF)=31.2 Hz), 130.5, 129.1 (q, J_(CF)=32.1Hz), 128.7, 125.1 (q, J_(CF)=3.7 Hz), 124.2 (q, J_(CF)=272.3 Hz, 2 C),123.2 (q, J_(CF)=3.8 Hz), 120.4 (q, J_(CF)=3.8 Hz), 116.1 (q, J_(CF)=3.7Hz), 51.7 (2 C), 45.6, 42.2, 24.2, 24.0, 17.8, 10.9; ¹⁹F NMR (376 MHz,CDCl₃) δ −62.4 (s, 3H), −62.6 (s, 3H); HRMS (ESI) m/z calcd forC₂₂H₂₃F₆N₂O ([M+H]⁺) 457.1709, found 457.1704.

1-(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one.A solution of 3-(3-(trifluoromethyl)phenyl)propiolic acid (0.100 g,0.467 mmol) and1-(5-chloro-2-(trifluoromethyl)phenyl)piperazinehydrochloride (0.155 g,0.514 mmol) in CH₂Cl₂ (4.7 mL) cooled to 0° C. was treated with Et₃N(0.26 mL, 1.87 mmol). The cooled solution was treated with T3P (50 wt. %solution in EtOAc, 0.49 mL, 0.701 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min, warmed to rt overnight, diluted with CH₂Cl₂(30 mL) and washed with H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The cruderesidue was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes), to give thecrude product that was contaminated with the piperazine startingmaterial (ca 10%). The product was dissolved in hot absolute EtOH thenstored overnight in the freezer (−20° C.) to facilitate crystallization.The supernatant was removed and the crystals were washed with hexanesand then dried under high vacuum overnight to give1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.168 g, 0.365 mmol, 78%) as a colorless solid: Mp 87.6-91.2° C.; IR(CH₂Cl₂) 2921, 2827, 2222, 1633, 1596, 1436, 1332, 1309, 1121, 1034, 695cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 7.71 (d, J=7.8 Hz, 1H),7.65 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H),7.26-7.22 (m, 2H), 3.95 (app t, J=5.0 Hz, 2H), 3.81 (app t, J=5.0 Hz,2H), 2.99 (app t, J=5.0 Hz, 2H), 2.92 (app t, J=5.0 Hz, 2H); ¹³C NMR(100 MHz, CDCl₃) δ 152.6, 138.8, 135.4, 131.2 (q, J_(CF)=33.0 Hz),129.2, 129.0 (q, J_(CF)=3.7 Hz), 128.6 (q, J_(CF)=5.4 Hz), 126.6 (q,J_(CF)=3.7 Hz), 125.8 (q, J_(CF)=29.5 Hz), 125.7, 124.7, 123.5 (q,J_(CF)=273.0 Hz), 123.2 (q, J_(CF)=272.5 Hz), 121.3, 88.9, 82.0, 53.6,52.7, 47.4, 41.8; ¹⁹F NMR (376 MHz, CDCl₃) δ −60.3 (s, 3 F), −63.0 (s, 3F); HRMS (ESI) m/z calcd for C₂₁H₁₆ClF₆N₂O ([M+H]⁺) 461.0850, found461.0849.

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(3-(trifluoromethyl)phenyl)cyclopropyl)-methanone.A solution of1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)-phenyl)prop-2-yn-1-one(0.0684 g, 0.148 mmol) in EtOAc (1.5 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0158 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc:hexanes)to give(Z)-1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0512 g, 0.111 mmol) as a colorless solid.

A solution of CrCl₂ (0.816 g, 0.940 mmol) and(Z)-1-(4-(5-chloro-2-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0512 g, 0.111 mmol) in dry degassed THF (1.6 mL) was sparged with Arfor 5 min and treated with CH₂ICl (0.064 mL, 0.553 mmol) at rt, heatedfor 2 d at 80° C., cooled to rt, diluted with EtOAc (50 mL), and washedwith 1 M aqueous HCl (3×20 mL). The organic layer was dried (MgSO₄),filtered and concentrated under reduced pressure. The crude residue waspurified by automated chromatography on SiO₂ (4 g column, liquid loadCH₂Cl₂, hexanes to 30% EtOAc/hexanes, product eluted at 20%EtOAc/hexanes) to give a clear oil that was filtered through basic Al₂O₃(eluting with 1:1 CH₂Cl₂/EtOAc), concentrated, and dried under highvacuum to give(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(3-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0409 g, 0.0858 mmol, 59% (2 steps) (100% purity by ELSD)) as a clearcolorless oil: IR (CH₂Cl₂) 2918, 1641, 1596, 1437, 1327, 1120, 1032,809, 702 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.54-7.50 (m, 3H), 7.44 (t,J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.20 (dd, J=8.5, 1.4 Hz, 1H),6.87 (d, J=1.6 Hz, 1H), 4.02 (d, J=13.0 Hz, 1H), 3.80 (d, J=13.0 Hz,1H), 3.51 (ddd, J=12.8, 9.8, 3.0 Hz, 1H), 3.13 (ddd, J=12.5, 9.8, 2.7Hz, 1H), 2.73 (td, J=7.7, 3.6 Hz, 2H), 2.52 (td, J=9.0, 7.0 Hz, 1H),2.25 (ddd, J=9.0, 8.4, 6.0 Hz, 1H), 2.21-2.15 (m, 1H), 1.97-1.90 (m,2H), 1.42 (td, J=8.4, 6.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.6,152.7, 138.9, 138.7, 130.6 (q, J_(CF)=32.1 Hz), 130.5, 128.7, 128.3 (q,J_(CF)=5.4 Hz), 125.8 (q, J_(CF)=29.4 Hz), 125.6, 125.1 (q, J_(CF)=3.8Hz), 124.6, 124.2 (q, J_(CF)=272.4 Hz), 123.5 (q, J_(CF)=272.9 Hz),123.2 (q, J_(CF)=3.7 Hz), 53.5, 53.0, 45.5, 42.1, 24.3, 23.9, 10.9; ¹⁹FNMR (376 MHz, CDCl₃) δ −60.4 (s, 3 F), −62.4 (s, 3 F); HRMS (ESI) m/zcalcd for C₂₂H₂₀ClF₆N₂O ([M+H]⁺) 477.1163, found 477.1166.

1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(pentafluoro4,6-sulfaneyl)phenyl)prop-2-yn-1-one.A solution of 3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid(0.100 g, 0.367 mmol) and 1-(1-(5-chloro-2-methylphenyl)piperazinehydrochloride (0.0999 g, 0.404 mmol) in CH₂Cl₂ (3.7 mL) cooled to 0° C.was treated with Et₃N (0.20 mL, 1.47 mmol). The cooled solution wastreated with T3P (50 wt. % solution in EtOAc, 0.39 mL, 0.551 mmol)dropwise and the reaction was stirred at 0° C. for 30 min, warmed to rtovernight, diluted with EtOAc (30 mL), washed with H₂O (20 mL), satd.aqueous NaHCO₃ (20 mL), dried (MgSO₄), filtered, and concentrated underreduced pressure. The crude residue was purified by automatedchromatography on SiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to30% EtOAc/hexanes), to give1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one(0.127 g, 0.272 mmol, 74%) as a pale yellow foam: IR (CDCl₃) 2981, 2222,1627, 1490, 1432, 1275, 832, 792, 727 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.76 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H),6.99 (dd, J=8.1, 2.1 Hz, 1H), 6.95 (d, J=2.1 Hz, 1H), 3.96 (app t, J=5.0Hz, 2H), 3.84 (app t, J=5.0 Hz, 2H), 2.97 (app t, J=5.0 Hz, 2H), 2.89(app t, J=5.0 Hz, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 154.4(quint, J_(CF)=18.3 Hz), 152.4, 151.6, 132.4, 132.1, 131.9, 131.0, 126.2(quint, J_(CF)=4.6 Hz), 124.1, 123.8, 119.8, 88.2, 83.2, 51.9, 51.3,47.4, 42.0, 17.3; ¹⁹F NMR (376 MHz, CDCl₃) δ 83.0 (quint, J=150.3 Hz, 1F), 62.4 (d, J=150.3 Hz, 4 F); HRMS (ESI) m/z calcd for C₂₀H₁₉ClF₅N₂OS([M+H]⁺) 465.0821, found 465.0819.

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(pentafluoro4,6-sulfaneyl)phenyl)-cyclopropyl)methanone.A solution of1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one(0.0850 g, 0.183 mmol) in EtOAc (1.8 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0195 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 2 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes,product eluted at 35% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-methylphenyl)-piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0811 g, 0.174 mmol) as a colorless solid.

A solution of CrCl₂ (0.126 g, 1.03 mmol) and(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0800 g, 0.171 mmol) in dry degassed THF (1.7 mL) was sparged with Arfor 5 min and added CH₂ICl (0.10 mL, 0.857 mmol) at rt, heated for 2 dat 80° C., cooled to rt, diluted with EtOAc (50 mL) and washed with 1 Maqueous HCl (3×20 mL). The organic layer was dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude residue was purified byautomated chromatography on SiO₂ (4 g column, liquid load CH₂Cl₂, 100%hexanes to 30% EtOAc/hexanes, product eluted at 30% EtOAc/hexanes) togive a clear oil that was filtered through basic Al₂O₃ (CH₂Cl₂/EtOAc,1:1), concentrated under reduced pressure, and dried under high vacuumto give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)-methanone(0.0451 g, 0.0938 mmol, 52% (2 steps) (100% purity by ELSD)) as acolorless solid: Mp 169.8-172.0° C.; IR (CH₂Cl₂) 2919, 1639, 1490, 1466,1438, 1225, 1035, 835, 750 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d,J=8.6 Hz, 2H), 7.25 (d, J=8.6 Hz, 2H), 7.06 (dd, J=8.1, 0.4 Hz, 1H),6.95 (dd, J=8.1, 2.1 Hz, 1H), 6.69 (d, J=2.1 Hz, 1H), 3.82 (bd, J=14.0Hz, 1H), 3.70-3.58 (m, 2H), 3.33 (ddd, J=12.4, 8.9, 3.0 Hz, 1H), 2.75(tdd, J=14.0, 7.7, 3.4 Hz, 2H), 2.50 (td, J=8.9, 7.0 Hz, 1H), 2.32-2.23(m, 2H), 2.20 (s, 3H), 2.10 (ddd, J=11.1, 8.2, 3.0 Hz, 1H), 1.91 (q,J=6.3 Hz, 1H), 1.44 (td, J=8.4, 5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ166.5, 152.1 (quint, J_(CF)=17.3 Hz), 151.6, 141.9, 131.9 (2 C), 130.9,127.7, 125.7 (quint, J_(CF)=4.6 Hz), 123.7, 119.5, 51.9, 51.5, 45.5,42.2, 24.6, 23.7, 17.3, 11.3; ¹⁹F NMR (376 MHz, CDCl₃) δ 84.8 (quint,J=150.4 Hz, 1 F), 63.2 (d, J=150.4 Hz, 4 F); HRMS (ESI) m/z calcd forC₂₁H₂₃ClF₅N₂OS ([M+H]⁺) 481.1134, found 481.1134.

Racemic(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)-cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm) injection volume 90 μL, 20mg/mL) to give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1S,2R)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)methanone(retention time 5.14 min) as a colorless viscous oil (100% purity byELSD): [α]¹⁷ _(D)−134.2 (c 0.60, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 7.66(d, J=8.7 Hz, 2H), 7.26 (overlap, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.96 (dd,J=8.1, 1.8 Hz, 1H), 6.70 (d, J=1.8 Hz, 1H), 3.87-3.79 (m, 1H), 3.73-3.58(m, 3H), 3.38-3.31 (m, 1H), 2.81-2.70 (m, 2H), 2.50 (q, J=8.7 Hz, 1H),2.33-2.24 (m, 2H), 2.20 (s, 3H), 2.16-2.08 (m, 1H), 1.91 (q, J=5.7 Hz,1H), 1.44 (td, J=8.1, 5.7 Hz, 1H). The enantiomeric excess was >99.9% ee(SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min, p=100 bar,220 nm; retention time: 5.1 min).

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1S,2R)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)-methanone(retention time 6.57 min) was obtained as a colorless viscous oil (100%purity by ELSD): [α]¹⁷ _(D)+136.3 (c 0.59, MeOH); ¹H NMR (300 MHz,CDCl₃) δ 7.66 (d, J=8.7 Hz, 2H), 7.26-7.24 (overlap, 2H), 7.06 (d, J=8.4Hz, 1H), 6.96 (dd, J=8.4, 1.8 Hz, 1H), 6.70 (d, J=1.8 Hz, 1H), 3.85-3.78(m, 1H), 3.67-3.61 (m, 2H), 3.39-3.30 (m, 1H), 2.81-2.70 (m, 2H), 2.50(q, J=8.7 Hz, 1H), 2.33-2.24 (m, 2H), 2.20 (s, 3H), 2.16-2.10 (m, 1H),1.91 (q, J=5.7 Hz, 1H), 1.44 (td, J=8.4, 5.7 Hz, 2H). The enantiomericexcess was >99.9% ee (SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7mL/min, p=100 bar, 220 nm; retention time: 6.5 min).

1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one.A solution of 3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid(0.100 g, 0.367 mmol) and1-(2-methyl-5-(trifluoromethyl)phenyl)piperazine hydrochloride (0.113 g,0.404 mmol) in CH₂Cl₂ (3.7 mL) cooled to 0° C. was treated with Et₃N(0.20 mL, 1.47 mmol). The cooled solution was treated with T3P (50 wt. %solution in EtOAc, 0.39 mL, 0.551 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min, warmed to rt overnight, diluted with EtOAc(30 mL), washed with H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The cruderesidue was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes), to give1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one(0.139 g, 0.278 mmol, 76%) as a tan foam: IR (CH₂Cl₂) 2920, 2222, 1632,1418, 1340, 1310, 1279, 1122, 839, 793 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.75 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.31-7.25 (m, 2H), 7.21(s, 1H), 3.98 (t, J=5.0 Hz, 2H), 3.85 (app t, J=5.0 Hz, 2H), 3.02 (appt, J=5.0 Hz, 2H), 2.92 (app t, J=5.0 Hz, 2H), 2.38 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 154.3 (quint, J_(CF)=18.1 Hz), 152.4, 150.9, 136.8, 132.4,131.5, 129.0 (q, J_(CF)=32.1 Hz), 126.2 (quint, J_(CF)=4.6 Hz), 124.1(q, J_(CF)=272.1 Hz), 124.0, 120.5 (q, J_(CF)=3.8 Hz), 116.0 (q,J_(CF)=3.6 Hz), 88.2, 83.1, 51.8, 51.3, 47.4, 41.9, 17.8; ¹⁹F NMR (376MHz, CDCl₃) δ 83.0 (quint, J=150.4 Hz, 1 F), 62.4 (d, J=150.2 Hz, 4 F),−62.3 (s, 3 F); HRMS (ESI) m/z calcd for C₂₁H₁₉F₈N₂OS ([M+H]⁺) 499.1085,found 499.1086.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(pentafluoro-λ6-sulfaneyl)-phenyl)cyclopropyl)methanone(JKJ741.040). A solution of1-(4-(2-methyl-5-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(4-(pentafluorosulfanyl)phenyl)prop-2-yn-1-one(0.100 g, 0.201 mmol) in EtOAc (2 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0214 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 2 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, 100% hexanes to 40% EtOAc/hexanes, product eluted at30% EtOAc/hexanes) to give(Z)-1-(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0765 g, 0.153 mmol, 76% (92% brsm) as a colorless foam.

To a flame dried 5 mL microwave vial containing anhydrous CrCl₂ (0.111g, 0.899 mmol) was treated with solution of(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0750 g, 0.150 mmol) in anhydrous THF (1.5 mL) and the mixture wassparged with Ar for 15 min and added CH₂ICl (0.087 mL, 0.749 mmol) at rtand under Ar atmosphere. The reaction mixture was stirred for 2 d at 80°C. The reaction was cooled to rt, quenched by the addition of EtOAc (50mL) and washed with 1 M aqueous HCl (3×20 mL). The organic layer wasdried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude material was purified by automated chromatography on SiO₂ (4 gcolumn, liquid load CH₂Cl₂, hexanes to 30% EtOAc/hexanes, product elutedat 30% EtOAc/hexanes) to give the product as a clear oil. The productwas filtered through basic Al₂O₃ (eluting with 1:1 CH₂Cl₂/EtOAc)concentrated to a colorless solid. The solid was recrystallized from hotcyclohexane (2×). The supernatant was removed and the crystals werewashed with rt cyclohexane (rt, 2×1 mL) and hexanes (2×1 mL) and driedunder high vacuum to give the product (0.0176 g, 0.0342 mmol, 18% (2steps) (100% purity by ELSD)) as a colorless solid: Mp 122.1-125.8° C.;IR (CH₂Cl₂) 2919, 1638, 1417, 1338, 1308, 1120, 824, 749 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 7.65 (d, J=8.8 Hz, 2H), 7.26-7.24 (m, 5H), 6.96 (s,1H), 3.85 (bd, J=13.0 Hz, 1H), 3.72-3.60 (m, 2H), 3.38-3.32 (m, 1H),2.86-2.75 (m, 2H), 2.51 (td, J=8.9, 7.0 Hz, 1H), 2.32-2.26 (m, 5H), 2.14(ddd, J=11.0, 8.6, 2.6 Hz, 1H), 1.92 (q, J=6.2 Hz, 1H), 1.45 (td, J=8.4,5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 152.2 (quint, J_(CF)=17.4Hz), 150.9, 141.8, 136.7, 131.4, 129.1 (q, J_(CF)=32.1 Hz), 127.7,125.7, 125.7 (quint, J_(CF)=4.6 Hz), 124.0 (q, J_(CF)=271.9 Hz), 120.4(q, J_(CF)=3.9 Hz), 115.7 (q, J_(CF)=3.8 Hz), 51.9, 51.4, 45.5, 42.2,24.6, 23.7, 17.9, 11.3; ¹⁹F NMR (376 MHz, CDCl₃) δ 84.6 (quint, J=149.9Hz, 1 F), 63.0 (d, J=149.8 Hz, 4 F), −62.4 (s, 3 F); HRMS (ESI) m/zcalcd for C₂₂H₂₃F₈N₂OS ([M+H]⁺) 515.1398, found 515.1378.

Racemic(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm) injection volume (90 μL, 20mg/mL) to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)((1S,2R)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)-cyclopropyl)methanone(retention time 3.40 min) as a colorless viscous oil (100% purity byELSD): [α]¹⁷ _(D)−119.1 (c 0.79, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 7.66(d, J=8.7 Hz, 2H), 7.25 (d, J=8.7 Hz, 3H), 6.97 (s, 1H), 3.89-3.80 (m,1H), 3.72-3.60 (m, 2H), 3.40-3.31 (m, 1H), 2.86-2.74 (m, 2H), 2.50 (q,J=8.4 Hz, 1H), 2.33-2.25 (m, 5H), 2.18-2.12 (m, 1H), 1.92 (q, J=6.0 Hz,1H), 1.44 (td, J=8.4, 6.0 Hz, 1H). The enantiomeric excess was >99.9% ee(SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min, p=100 bar,220 nm; retention time: 3.3 min).

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)((1R,2S)-2-(4-(pentafluoro-λ6-sulfaneyl)-phenyl)cyclopropyl)methanone(retention time 3.65 min) was obtained as a colorless viscous oil (100%purity by ELSD): [α]¹⁷ _(D)+117.0 (c 0.87, MeOH); ¹H NMR (300 MHz,CDCl₃) δ 7.66 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 3H), 6.97 (s, 1H),3.88-3.82 (m, 2H), 3.69-3.63 (m, 3H), 3.40-3.31 (m, 2H), 2.89-2.70 (m,3H), 2.50 (q, J=8.4 Hz, 2H), 2.34-2.25 (m, 5H), 2.20-2.12 (m, 1H), 1.92(q, J=6.0 Hz, 1H), 1.44 (td, J=8.4, 6.0 Hz, 1H). The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min,p=100 bar, 220 nm; retention time: 3.7 min).

1-(4-(5-Chloro-2-methylphenyl)piperazine-1-yl)-3-(3-(pentafluoro4,6-sulfaneyl)phenyl)prop-2-yn-1-one.A solution of 3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid(0.100 g, 0.367 mmol) and 1-(1-(5-chloro-2-methylphenyl)piperazinehydrochloride (0.0999 g, 0.404 mmol) in CH₂Cl₂ (3.7 mL) cooled to 0° C.was treated with Et₃N (0.20 mL, 1.47 mmol). The cooled solution wastreated with T3P (50 wt. % solution in EtOAc, 0.39 mL, 0.551 mmol)dropwise and the reaction was stirred at 0° C. for 30 min and allowed towarm to rt overnight. The reaction was diluted with EtOAc (30 mL) andwashed with H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried (MgSO₄),filtered, and concentrated under reduced pressure. The crude residue waspurified by automated chromatography on SiO₂ (4 g column, liquid loadCH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes), to give1-(4-(5-chloro-2-methylphenyl)piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one(0.113 g, 0.244 mmol, 66%) as a pale yellow solid: Mp 127.9-133.0° C.;IR (CDCl₃) 2921, 2219, 1627, 1432, 1288, 1223, 1041, 838, 797, 728 cm⁻¹;¹H NMR (400 MHz, CDCl₃) δ 7.94 (t, J=2.0 Hz, 1H), 7.80 (ddd, J=8.4, 2.0,0.8 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 7.11 (d,J=8.1 Hz, 1H), 6.99 (dd, J=8.1, 2.1 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H),3.97 (app t, J=5.0 Hz, 2H), 3.84 (app t, J=5.0 Hz, 2H), 2.98 (app t,J=5.0 Hz, 2H), 2.89 (app t, J=5.0 Hz, 2H), 2.29 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 153.8 (quint, J_(CF)=18.5 Hz), 152.4, 151.6, 135.1, 132.1,131.9, 131.0, 129.7 (quint, J_(CF)=7.1 Hz), 129.0, 127.3 (quint,J_(CF)=4.5 Hz), 123.8, 121.6, 119.8, 88.4, 82.3, 51.9, 51.3, 47.4, 42.0,17.3; ¹⁹F NMR (376 MHz, CDCl₃) δ 82.9 (quint, J=150.6 Hz, 1 F), 62.6 (d,J=150.5 Hz, 4 F); HRMS (ESI) m/z calcd for C₂₀H₁₉ClF₅N₂OS ([M+H]⁺)465.0821, found 465.0821.

(4-(5-Chloro-2-methylphenyl)piperazine-1-yl)((1RS,2SR)-2-(3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)methanone.A solution of1-(4-(5-chloro-2-methylphenyl)piperazine-1-yl)-3-(4-(pentafluorosulfanyl)phenyl)prop-2-yn-1-one(0.0930 g, 0.200 mmol) in EtOAc (2 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0213 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc) and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes,product eluted at 20% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-methylphenyl)-piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0470 g, 0.101 mmol) as a colorless solid.

To a flame dried 5 mL microwave vial containing CrCl₂ (0.0742 g, 0.604mmol) was added a solution of(Z)-1-(4-(5-chloro-2-methylphenyl)piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0470 g, 0.101 mmol) in dry degassed THF (1 mL) and the mixture wassparged with Ar for 15 min and added CH₂Icl (0.058 mL, 0.503 mmol) atrt, heated for 2 d at 80° C. The reaction was cooled to rt, diluted withEtOAc (50 mL) and washed with 1 M aqueous HCl (3×20 mL). The organiclayer was dried (MgSO₄), filtered and concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes,product eluted at 20% EtOAc/hexanes) to give the product as a clear oil.The product was filtered through basic Al₂O₃ (CH₂Cl₂/EtOAc, 1:1)concentrated and dried under high vacuum to give(4-(5-chloro-2-methylphenyl)piperazine-1-yl)((1RS,2SR)-2-(3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)methanone(0.0182 g, 0.0378 mmol, 19% (2 steps) (100% purity by ELSD)) as acolorless solid: Mp 112.9-116.1° C.; IR (CH₂Cl₂) 2854, 1640, 1490, 1439,1225, 1036, 841 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.59 (m, 2H), 7.38(t, J=8.1 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.95(dd, J=8.1, 2.1 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 3.84 (bd, J=12.8 Hz,1H), 3.76-3.71 (m, 1H), 3.61 (ddd, J=12.8, 8.9, 3.2 Hz, 1H), 3.29 (ddd,J=12.8, 9.0, 3.1 Hz, 1H), 2.80-2.71 (m, 2H), 2.53 (td, J=8.9, 6.9 Hz,1H), 2.31-2.23 (m, 2H), 2.20 (s, 3H), 2.15-2.09 (m, 1H), 1.91 (q, J=6.2Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.6,153.9 (quint, J_(CF)=16.8 Hz), 151.8, 139.0, 132.0, 131.8, 131.0, 130.2,128.6, 125.9 (quint, J_(CF)=4.5 Hz), 124.0 (quint, J_(CF)=4.6 Hz),123.7, 119.7, 51.8, 51.6, 45.6, 42.2, 24.1, 24.0, 17.3, 11.0; ¹⁹F NMR(376 MHz, CDCl₃) δ 84.7 (quint, J=150.1 Hz, 1 F), 62.9 (d, J=149.9 Hz, 4F); HRMS (ESI) m/z calcd for C₂₁H₂₃ClF₅N₂OS ([M+H]⁺) 481.1134, found481.1133.

1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)-3-(3-(pentafluoro4,6-sulfaneyl)phenyl)-prop-2-yn-1-one.A solution of 3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)propiolic acid(0.100 g, 0.367 mmol) and1-(2-methyl-5-(trifluoromethyl)phenyl)piperazine hydrochloride (0.113 g,0.404 mmol) in CH₂Cl₂ (3.7 mL) cooled to 0° C. was treated with Et₃N(0.20 mL, 1.47 mmol). The cooled solution was treated with T3P (50 wt. %solution in EtOAc, 0.39 mL, 0.551 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min, warmed to rt overnight, diluted with EtOAc(30 mL), washed with H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The cruderesidue was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes), to give1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one(0.150 g, 0.300 mmol, 82%) as a tan foam: IR (CH₂Cl₂) 2919, 2825, 2219,1629, 1418, 1309, 1152, 1119, 840, 797, 730 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 7.94 (t, J=1.8 Hz, 1H), 7.81 (dt, J=8.2, 1.1 Hz, 1H), 7.70 (d,J=7.8 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.29 (q, J=7.8 Hz, 2H), 7.22 (s,1H), 4.00 (app t, J=5.0 Hz, 2H), 3.87 (app t, J=5.0 Hz, 2H), 3.04 (appt, J=5.0 Hz, 2H), 2.94 (app t, J=5.0 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 153.8 (quint, J_(CF)=18.2 Hz), 152.5, 150.9, 136.8, 135.1,131.6, 129.7 (quint, J_(CF)=4.7 Hz), 129.1 (q, J_(CF)=32.3 Hz), 129.1,127.4 (quint, J_(CF)=4.7 Hz), 124.1 (q, J_(CF)=271.8 Hz), 121.5, 120.6(q, J_(CF)=3.9 Hz), 116.1 (q, J_(CF)=3.6 Hz), 88.4, 82.3, 51.9, 51.3,47.4, 42.0, 17.9; ¹⁹F NMR (376 MHz, CDCl₃) δ 82.9 (quint, J=150.6 Hz, 1F), 62.6 (d, J=150.4 Hz, 4 F), −62.3 (s, 3 F); HRMS (ESI) m/z calcd forC₂₁H₁₉F₈N₂OS ([M+H]⁺) 499.1085, found 499.1086.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)((1RS,2SR)-2-(3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)methanone.A solution of1-(4-(2-methyl-5-(trifluoromethyl)phenyl)-piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-yn-1-one(0.100 g, 0.201 mmol) in EtOAc (2 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0214 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 2 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes,product eluted at 30% EtOAc/hexanes) to give(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0938 g, 0.187 mmol) as a colorless foam.

A solution of CrCl₂ (0.138 g, 1.12 mmol) and(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)-piperazine-1-yl)-3-(3-(pentafluoro-λ6-sulfaneyl)phenyl)prop-2-en-1-one(0.0938 g, 0.187 mmol) in dry degassed THF (1.9 mL) (degassed bysparging with Ar for 15 min) was treated with CH₂ICl (0.11 mL, 0.937mmol) at rt, heated for 2 d at 80° C., cooled to rt, diluted with EtOAc(50 mL), and washed with 1 M aqueous HCl (3×20 mL). The organic layerwas dried (MgSO₄), filtered and concentrated under reduced pressure. Thecrude residue was purified by automated chromatography on SiO₂ (4 gcolumn, liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes, producteluted at 30% EtOAc/hexanes), filtered through basic Al₂O₃(CH₂Cl₂/EtOAc, 1:1), concentrated under reduced pressure, and driedunder high vacuum to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazine-1-yl)((1RS,2SR)-2-(3-(pentafluoro-λ6-sulfaneyl)-phenyl)cyclopropyl)methanone(0.0641 g, 0.125 mmol, 62% (2 steps) (100% purity by ELSD)) as a paleyellow oil: IR (CH₂Cl₂) 2917, 1638, 1438, 1417, 1337, 1307, 1120, 835,758 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.58 (m, 2H), 7.38 (t, J=7.8Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.24-7.21 (m, 2H), 6.96 (s, 1H), 3.93(d, J=13.0 Hz, 1H), 3.79 (dt, J=13.0, 3.8 Hz, 1H), 3.60 (ddd, J=12.6,9.2, 3.1 Hz, 1H), 3.25 (ddd, J=12.6, 9.2, 3.0 Hz, 1H), 2.79 (ddt,J=20.7, 11.9, 3.8 Hz, 2H), 2.53 (td, J=8.9, 6.9 Hz, 1H), 2.31-2.20 (m,5H), 2.16-2.10 (m, 1H), 1.92 (q, J=6.2 Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz,1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 153.9 (quint, J_(CF)=16.9 Hz),151.0, 139.0, 136.8, 131.3, 130.3, 129.0 (q, J_(CF)=33.1 Hz), 128.5,125.7 (quint, J_(CF)=4.6 Hz), 124.2 (q, J_(CF)=272.0 Hz), 123.9 (quint,J_(CF)=4.6 Hz), 120.3 (q, J_(CF)=3.9 Hz), 115.9 (q, J_(CF)=3.6 Hz),51.7, 51.6, 45.5, 42.2, 24.0 (2 C), 24.0, 17.8, 10.9; ¹⁹F NMR (376 MHz,CDCl₃) δ 84.5 (quint, J=150.0 Hz, 1 F), 62.7 (d, J=149.8 Hz, 4 F), −62.4(s, 3 F); HRMS (ESI) m/z calcd for C₂₂H₂₃F₈N₂OS ([M+H]⁺) 515.1398, found515.1380.

Racemic(4-(2-methyl-5-(trifluoromethyl)phenyl)-101-iperazine-1-yl)((1RS,2SR)-2-(3-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm) injection volume 90 μL, 20mg/mL) to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(3-(pentafluoro-λ6-sulfaneyl)phenyl)-cyclopropyl)methanone(retention time 3.25 min) as a colorless viscous oil (100% purity byELSD): [α]¹⁸ _(D)−104.7 (c 0.84, MeOH); ¹H NMR (300 MHz, CDCl₃) δ7.62-7.58 (m, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.31-7.24 (m, 3H), 6.96 (s,1H), 3.94-3.89 (m, 1H), 3.81-3.75 (m, 1H), 3.65-3.56 (m, 1H), 3.31-3.22(m, 1H), 2.84-2.74 (m, 2H), 2.53 (td, J=9.3, 6.9 Hz, 1H), 2.32-2.21 (m,5H), 2.19-2.11 (m, 1H), 1.93 (q, J=5.7 Hz, 1H), 1.43 (td, J=8.4, 5.7 Hz,1H). The enantiomeric excess was >99.9% ee (SFC Chiralpak-IC (250×10mm); 30% Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm; retention time: 3.3min).

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(3-(pentafluoro-λ6-sulfaneyl)phenyl)-cyclopropyl)methanone(retention time 3.60 min) was obtained as a colorless viscous oil (100%purity by ELSD): [α]¹⁸ _(D)+103.4 (c 0.87, MeOH); ¹H NMR (300 MHz,CDCl₃) δ 8.54-7.81 (m, 2H), 7.62-7.59 (m, 2H), 7.38 (t, J=7.8 Hz, 1H),7.31-7.24 (m, 3H), 6.96 (s, 1H), 3.94-3.88 (m, 1H), 3.81-3.75 (m, 1H),3.65-3.56 (m, 1H), 3.31-3.22 (m, 1H), 2.84-2.74 (m, 2H), 2.53 (td,J=9.0, 7.2 Hz, 1H), 2.32-2.22 (m, 5H), 2.18-2.11 (m, 1H), 1.93 (q, J=5.7Hz, 1H), 1.43 (td, J=8.4, 5.7 Hz, 1H). The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC (250×10 mm); 30% Methanol:CO₂, 7 mL/min,p=100 bar, 220 nm; retention time: 3.6 min).

1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-one.A solution of methyl 3-(5-chloropyridin-2-yl)propionate (0.500 g, 2.18mmol) in THF (4 mL) was treated with 2 M NaOH (1.2 mL, 2.40 mmol) andthe mixture was stirred at rt for 3 h, acidified with 1 M aqueous HCl,and extracted with EtOAc (3×20 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated under reduced pressure to givethe product (0.422 g, 1.96 mmol) as a colorless solid. This solid wastaken on to the coupling reaction with no further purification.

A solution of 3-(6-(trifluoromethyl)pyridin-3-yl)propionic acid (0.422g, 1.96 mmol) and 1-(2-methyl-5-(trifluoromethyl)phenyl)piperazinehydrochloride (0.661 g, 2.35 mmol) in CH₂Cl₂ (19 mL) cooled to 0° C. wastreated Et₃N (0.83 mL, 5.88 mmol). The cooled solution was treated withT3P (50% solution in EtOAc) (2.1 mL, 2.94 mmol) dropwise and thereaction was stirred at 0° C. for 30 min, warmed to rt overnight,diluted with EtOAc (50 mL), washed with H₂O (20 mL), satd. aqueousNaHCO₃ (20 mL), dried (MgSO₄), filtered, and concentrated under reducedpressure. The crude material was purified by chromatography on SiO₂ (4 gcolumn, 1:1 hexanes:EtOAc), to give the product (0.781 g, 1.77 mmol, 81%(2 steps)) as a pale yellow solid: Mp 110.7-113.5° C.; IR (CH₂Cl₂) 3652,2981, 2890, 1635, 1382, 1337, 1240, 1150, 1087, 956 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 8.85 (dd, J=1.6, 0.6 Hz, 1H), 8.04 (ddd, J=8.2, 1.6, 0.6Hz, 1H), 7.72 (dd, J=8.2, 0.6 Hz, 1H), 7.32-7.26 (m, 2H), 7.21 (s, 1H),3.99 (t, J=5.0 Hz, 2H), 3.87 (t, J=5.0 Hz, 2H), 3.04 (t, J=5.0 Hz, 2H),2.95 (t, J=5.0 Hz, 2H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.5,152.0, 150.8, 148.2 (q, J_(CF)=35.3 Hz), 140.7, 136.8, 131.6, 129.1 (q,J_(CF)=32.3 Hz), 124.1 (q, J_(CF)=272.1 Hz), 121.0 (q, J_(CF)=274.4 Hz),120.7, 120.6 (q, J_(CF)=3.9 Hz), 120.0 (q, J_(CF)=2.8 Hz), 116.1 (q,J_(CF)=3.6 Hz), 85.6, 51.8, 51.3, 47.4, 42.0, 17.9; ¹⁹F NMR (376 MHz,CDCl₃) δ −62.3 (s, 3 F). −68.2 (s, 3 F); HRMS (ESI) m/z calcd forC₂₁H₁₈F₆N₃O ([M+H]⁺) 442.1349, found 442.1345.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)methanone.A solution of1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)prop-2-yn-1-one(0.720 g, 1.63 mmol) in EtOAc (16 mL) at rt was treated with quinoline(1.0 mL, 8.16 mmol) and 5% Pd/BaSO₄ (0.0347 g, 0.0163 mmol, equivalentto 1 mol % Pd) and the reaction was stirred under an atmosphere of H₂(3× backfill cycles) for 4 h. Analysis by TLC (hexanes/EtOAc, 1:1)indicated that the starting material had been mostly consumed. Thereaction was filtered (eluting with EtOAc), and the filtrate was washedwith 1 M aqueous HCl (3×30 mL), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude residue was purified bychromatography on SiO₂ (hexanes/EtOAc, 1:1 to EtOAc) to give(Z)-1-(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)prop-2-en-1-one(0.640 g, 1.44 mmol) as a yellow/orange oil.

A solution of CrCl₂ (1.06 g, 8.66 mmol) and(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)prop-2-en-1-one(0.640 g, 1.44 mmol) in dry degassed THF (14 mL) was sparged with Ar for5 min and treated with CH₂ICl (0.83 mL, 7.22 mmol) at rt and under Aratmosphere. The reaction mixture was stirred for 2 d at 80° C., cooledto rt, diluted with EtOAc (50 mL), and washed with 1 M aqueous HCl (3×20mL). The organic layer was dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude material was purified bychromatography on SiO₂ (4:1, EtOAc:hexanes), filtered through basicAl₂O₃ (eluting with EtOAc) concentrated under reduced pressure, anddried under high vacuum to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)methanone(0.280 g, 0.612 mmol, 37% (2 steps) (100% purity by ELSD)) as an orangeoil: IR (CH₂Cl₂) 2981, 1640, 1418, 1339, 1309, 1166, 1126, 1035, 828cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.64 (s, 1H), 7.60 (t, J=2.0 Hz, 2H),7.24 (t, J=2.0 Hz, 2H), 7.02 (s, 1H), 3.78-3.65 (m, 3H), 3.53-3.46 (m,1H), 2.92-2.87 (m, 1H), 2.80-2.75 (m, 1H), 2.59-2.53 (m, 1H), 2.47-2.35(m, 4H), 2.30 (s, 3H), 1.95 (q, J=5.6 Hz, 1H), 1.49 (td, J=8.4, 5.6 Hz,1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.4, 150.8, 150.5, 146.3 (q,J_(CF)=34.8 Hz), 136.9, 136.7, 135.5, 131.4, 129.1 (q, J_(CF)=32.2 Hz),124.1 (q, J_(CF)=272.1 Hz), 121.6 (q, J_(CF)=273.7 Hz), 120.4 (q,J_(CF)=3.9 Hz), 119.8 (q, J_(CF)=2.6 Hz), 115.9 (q, J_(CF)=3.7 Hz),52.0, 51.5, 45.6, 42.3, 23.7, 21.5, 17.9, 11.0; ¹⁹F NMR (376 MHz, CDCl₃)δ −62.4 (s, 3 F), −67.8 (s, 3 F); HRMS (ESI) m/z calcd for C₂₂H₂₂F₆N₃O([M+H]⁺) 458.1662, found 458.1660.

Racemic(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (15%Methanol/CO₂, 7 mL/min, 220 nm, p=100 bar, 20 mg/mL in MeOH) to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)methanone(retention time 7.65 min) as a colorless solid (100% purity by ELSD):[α]¹⁹ _(D)−134.8 (c 0.90, MeOH); ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H),7.60 (s, 2H), 7.26 (s, 4H), 7.04 (s, 1H), 3.75-3.64 (m, 3H), 3.55-3.47(m, 1H), 2.94-2.87 (m, 1H), 2.82-2.74 (m, 1H), 2.56 (q, J=8.4 Hz, 1H),2.49-2.34 (m, 3H), 2.31 (s, 3H), 1.96 (q, J=5.8 Hz, 1H), 1.50 (td,J=8.4, 5.8 Hz, 1H). The enantiomeric excess was >99.9% ee (SFCChiralpak-IC (250×10 mm); 15% Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm;retention time: 7.8 min).

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(6-(trifluoromethyl)pyridin-3-yl)-cyclopropyl)methanone(retention time 8.38 min) was obtained as a colorless solid (100% purityby ELSD): [α]¹⁹ _(D)+128.2 (c 1.08, MeOH); ¹H NMR (300 MHz, CDCl₃) δ8.64 (s, 1H), 7.60 (s, 2H), 7.26 (s, 2H), 7.04 (s, 1H), 3.77-3.63 (m,3H), 3.55-3.47 (m, 1H), 2.93-2.87 (m, 1H), 2.81-2.75 (m, 1H), 2.61-2.52(m, 1H), 2.50-2.35 (m, 2H), 2.31 (s, 3H), 1.96 (q, J=5.8 Hz, 1H), 1.50(td, J=8.4, 5.8 Hz, 1H). The enantiomeric excess was >99.9% ee (SFCChiralpak-IC (250×10 mm); 15% Methanol:CO₂, 7 mL/min, p=100 bar, 220 nm;retention time: 8.4 min).

1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one.A solution of 3-(5-methylthiophen-2-yl)propiolic acid (0.0750 g, 0.451mmol) and 1-(5-chloro-2-methylphenyl)-piperazine hydrochloride (0.134 g,0.542 mmol) in CH₂Cl₂ (4.5 mL) cooled to 0° C. was treated with Et₃N(0.19 mL, 1.35 mmol). The cooled solution was treated with T3P (50 wt. %solution in EtOAc, 0.48 mL, 0.677 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min, warmed to rt overnight, diluted with CH₂Cl₂(30 mL), washed with 1 M aqueous HCl (20 mL), dried (MgSO₄), filtered,and concentrated under reduced pressure. The crude residue was purifiedby automated chromatography on SiO₂ (4 g column, liquid load CH₂Cl₂,hexanes to 40% EtOAc/hexanes), to give1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one(0.0620 g, 0.173 mmol, 38%) as a colorless solid: Mp 114.4-116.0° C.; IR(CH₂Cl₂) 2919, 2197, 1643, 1593, 1489, 1426, 1224, 1025, 806 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.24 (d, J=3.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H),6.98 (dd, J=8.1, 1.9 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.69 (dd, J=3.6,0.8 Hz, 1H), 3.91 (app t, J=5.0 Hz, 2H), 3.81 (app t, J=5.0 Hz, 2H),2.94 (app t, J=5.0 Hz, 2H), 2.86 (app t, J=5.0 Hz, 2H), 2.49 (s, 3H),2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.1, 151.7, 145.5, 135.7,132.0, 131.8, 130.9, 125.8, 123.6, 119.7, 117.4, 85.4, 84.5, 51.8, 51.3,47.2, 41.8, 17.4, 15.5; HRMS (ESI) m/z calcd for C₁₉H₂₀ClN₂OS ([M+H]⁺)359.0979, found 359.0978.

(Z)-1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one.A solution of1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one(0.0620 g, 0.173 mmol) in EtOAc (1.7 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.00735 g, equivalent to 2 mol% Pd) and quinoline (10 μL, 0.172 mmol). The reaction was placed under aballoon of H₂ (4 vacuum/backfill cycles) and stirred at rt for 6 h,filtered through Celite, washed (EtOAc), and the combined filtrates werewashed with 1 M aqueous HCl, dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The crude residue was purified by automatedchromatography on SiO₂ (4 g column, liquid load CH₂Cl₂, 10%EtOAc/hexanes to 40% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one(0.0263 g, 0.0729 mmol, 42% (100% purity by ELSD)) as a colorless solid:Mp 113.2-116.4° C.; IR (CH₂Cl₂) 2917, 2818, 1643, 1593, 1489, 1435,1226, 1039, 805 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.09 (dd, J=8.1, 0.8 Hz,1H), 6.98-6.95 (m, 2H), 6.90 (d, J=2.1 Hz, 1H), 6.75 (d, J=12.4 Hz, 1H),6.67 (dq, J=3.5, 1.1 Hz, 1H), 5.88 (d, J=12.4 Hz, 1H), 3.87 (app t,J=5.0 Hz, 2H), 3.67 (app t, J=5.0 Hz, 2H), 2.90 (app t, J=5.0 Hz, 2H),2.78 (app t, J=5.0 Hz, 2H), 2.48 (d, J=0.8 Hz, 3H), 2.26 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 166.9, 151.9, 143.7, 135.9, 132.0, 131.7, 131.2,130.9, 128.6, 125.2, 123.6, 119.7, 117.2, 51.7, 51.3, 46.6, 41.7, 17.4,15.5; HRMS (ESI) m/z calcd for C₁₉H₂₂ClN₂OS ([M+H]⁺) 361.1136, found361.1135.

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(5-methylthiophen-2-yl)cyclopropyl)-methanone.A solution of CrCl₂ (0.0511 g, 0.416 mmol) and(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one(0.0250 g, 0.0693 mmol) in dry degassed THF (0.7 mL) was sparged with Arfor 5 min and treated with CH₂ICl (40 uL, 0.346 mmol) at rt, heated for20 h at 80° C., cooled to rt, combined, diluted with Et₂O (50 mL), andwashed with 1 M aqueous HCl (3×20 mL). The organic layer was dried(MgSO₄), filtered and concentrated under reduced pressure. The cruderesidue was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes) to give the product asa yellow oil. The product was filtered through basic Al₂O₃ (eluting with1:1 CH₂Cl₂/EtOAc) concentrated under reduced pressure and dried underhigh vacuum to give(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2SR)-2-(5-methylthiophen-2-yl)cyclopropyl)methanone(0.0154 g, 0.0411 mmol, 59% (100% purity by ELSD)) as a pale yellow oil:IR (CH₂Cl₂) 2918, 1643, 1593, 1490, 1462, 1436, 1226, 1029, 802 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.08 (dd, J=8.1, 0.4 Hz, 1H), 6.97 (dd, J=8.1,2.1 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 6.57-6.55 (m, 2H), 3.96 (d, J=13.0Hz, 1H), 3.85 (dt, J=13.0, 3.5 Hz, 1H), 3.63 (ddd, J=13.0, 8.9, 3.5 Hz,1H), 3.34 (ddd, J=13.0, 9.0, 3.2 Hz, 1H), 2.79 (ddt, J=19.3, 11.2, 4.1Hz, 2H), 2.52 (td, J=8.9, 6.8 Hz, 1H), 2.45-2.36 (m, 5H), 2.24 (s, 3H),2.16 (ddd, J=8.9, 8.2, 6.3 Hz, 1H), 1.77 (td, J=6.3, 5.6 Hz, 1H), 1.38(ddd, J=8.9, 8.2, 5.6 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 152.1,138.2, 137.5, 131.9, 131.7, 131.1, 125.0, 124.1, 123.5, 119.7, 51.8,51.7, 45.7, 42.4, 24.1, 19.3, 17.3, 15.3, 12.2; HRMS (ESI) m/z calcd forC₁₉H₂₄ClN₂OS ([M+H]⁺) 375.1292, found 375.1292.

1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one.A solution of 3-(5-methylthiophen-2-yl)propiolic acid (0.0592 g, 0.356mmol) and 1-(2-methyl-5-(trifluoromethyl)phenyl)piperazine hydrochloride(0.100 g, 0.356 mmol) in CH₂Cl₂ (3.6 mL) cooled to 0° C. was treatedwith Et₃N (0.20 mL, 1.42 mmol). The cooled solution was treated with T3P(50 wt. % solution in EtOAc, 0.38 mL, 0.534 mmol) dropwise and thereaction was stirred at 0° C. for 30 min, warmed to rt overnight,diluted with CH₂Cl₂ (30 mL), washed with 1 M aqueous HCl (20 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The crudematerial was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes), to give1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one(0.0685, 0.175 mmol, 49% (100% purity by ELSD)) as a yellow solid. Mp145.7-149.3° C.; IR (CH₂Cl₂) 2919, 2199, 1635, 1420, 1340, 1309, 1120,1029, 955, 732 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.24 (m, 3H), 7.21(s, 1H), 6.69 (dd, J=3.6, 0.8 Hz, 1H), 3.94 (app t, J=5.0 Hz, 2H), 3.83(app t, J=5.0 Hz, 2H), 3.01 (app t, J=5.0 Hz, 2H), 2.91 (app t, J=5.0Hz, 2H), 2.49 (d, J=0.8 Hz, 3H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)δ 153.2, 151.0, 145.5, 136.8, 135.7, 131.5, 129.0 (q, J_(CF)=32.2 Hz),125.9, 124.1 (q, J_(CF)=272.1 Hz), 120.4 (q, J_(CF)=3.8 Hz), 117.4,116.0 (q, J_(CF)=3.6 Hz), 85.4, 84.5, 51.8, 51.3, 47.3, 41.8, 17.9,15.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.2 (s, 3 F); HRMS (ESI) m/z calcdfor C₂₀H₂₀F₃N₂OS ([M+H]⁺) 393.1243, found 393.1241.

(Z)-1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one.A solution of1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one(0.0650 g, 0.166 mmol) in EtOAc (1.7 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0176 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes,product eluted at 20% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)-phenyl)prop-2-en-1-one(0.0443 g, 0.112 mmol, 68%) as a colorless solid: Mp 125.8-128.1° C.; IR(CH₂Cl₂) 2919, 2857, 1635, 1435, 1339, 1308, 1118, 1040, 806 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.28 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.0, 1.3 Hz,1H), 7.15 (s, 1H), 6.96 (d, J=3.5 Hz, 1H), 6.76 (d, J=12.4 Hz, 1H), 6.67(dq, J=3.5, 1.0 Hz, 1H), 5.89 (d, J=12.4 Hz, 1H), 3.89 (app t, J=4.8 Hz,2H), 3.69 (app t, J=4.8 Hz, 2H), 2.94 (app t, J=4.8 Hz, 2H), 2.82 (appt, J=4.8 Hz, 2H), 2.47 (d, J=1.0 Hz, 3H), 2.36 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 166.9, 151.2, 143.7, 136.8, 135.9, 131.5, 131.2, 128.9 (q,J_(CF)=32.2 Hz), 128.7, 125.2, 124.1 (q, J_(CF)=272.1 Hz), 120.3 (q,J_(CF)=3.7 Hz), 117.2, 115.9 (q, J_(CF)=3.7 Hz), 51.6, 51.3, 46.6, 41.7,17.9, 15.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.2 (s, 3 F); HRMS (ESI) m/zcalcd for C₂₀H₂₂F₃N₂OS ([M+H]⁺) 395.1399, found 393.1399.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(5-methylthiophen-2-yl)cyclopropyl)methanone.A solution of CrCl₂ (0.105 g, 0.851 mmol) and(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0420 g, 0.142 mmol) in dry degassed THF (1.1 mL) was sparged with Arfor 5 min and treated with CH₂ICl (62 uL, 0.532 mmol) at rt, heated for22 h at 80° C., cooled to rt, diluted with Et₂O (50 mL), and washed with1 M aqueous HCl (3×20 mL). The organic layer was dried (MgSO₄), filteredand concentrated under reduced pressure. The crude residue was purifiedby automated chromatography on SiO₂ (4 g column, liquid load CH₂Cl₂,100% hexanes to 40% EtOAc/hexanes) to give a clear oil that was filteredthrough basic Al₂O₃ (eluting with 1:1 CH₂Cl₂/EtOAc), concentrated underreduced pressure, and dried under high vacuum to give(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(5-methylthiophen-2-yl)cyclopropyl)methanone(0.0187 g, 0.0458 mmol, 43% (100% purity by ELSD)) as pale yellowviscous oil: IR (CH₂Cl₂) 2921, 2822, 1639, 1464, 1434, 1417, 1337, 1306,1116, 1079, 1031, 801 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, J=8.4 Hz,1H), 7.24 (dd, J=8.4, 1.4 Hz, 1H), 7.04 (s, 1H), 6.58 (t, J=4.7 Hz, 1H),6.55 (dt, J=3.5, 1.0 Hz, 1H), 4.00 (bd, J=13.0 Hz, 1H), 3.88 (dt,J=13.0, 3.5 Hz, 1H), 3.64 (ddd, J=12.4, 9.0, 3.2 Hz, 1H), 3.34 (ddd,J=13.0, 9.2, 2.9 Hz, 1H), 2.82 (ddt, J=19.4, 11.6, 3.7 Hz, 2H), 2.53(td, J=8.6, 6.6 Hz, 1H), 2.48-2.40 (m, 1H), 2.38 (d, J=1.0 Hz, 3H), 2.34(s, 3H), 2.17 (td, J=8.6, 6.6 Hz, 1H), 1.77 (q, J=6.0 Hz, 1H), 1.38 (td,J=8.6, 5.3 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.2, 151.4, 138.3,137.6, 136.9, 131.4, 128.9 (q, J_(CF)=32.0 Hz), 124.9, 124.3 (q,J_(CF)=272.1 Hz), 124.2, 120.3 (q, J_(CF)=4.0 Hz), 116.0 (q, J_(CF)=3.7Hz), 51.8, 51.7, 45.7, 42.3, 24.1, 19.4, 17.9, 15.1, 12.3; ¹⁹F NMR (376MHz, CDCl₃) δ −62.2 (s, 3 F); HRMS (ESI) m/z calcd for C₂₁H₂₄F₃N₂OS([M+H]⁺) 409.1556, found 409.1555.

1-(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one.A solution of 3-(5-methylthiophen-2-yl)propiolic acid (0.0770 g, 0.463mmol) and 1-(5-chloro-2-(trifluoromethyl)phenyl)piperazine hydrochloride(0.153 g, 0.510 mmol) in CH₂Cl₂ (4.6 mL) cooled to 0° C. was treatedwith Et₃N (0.26 mL, 1.85 mmol). The cooled solution was treated with T3P(50 wt. % solution in EtOAc, 0.49 mL, 0.695 mmol) dropwise and thereaction was stirred at 0° C. for 30 mm, warmed to rt overnight, dilutedwith CH₂Cl₂ (30 mL), washed with H₂O (20 mL), satd. aqueous NaHCO₃ (20mL), dried (MgSO₄), filtered, and concentrated under reduced pressure.The crude material was purified by automated chromatography on SiO₂ (4 gcolumn, liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes), to give1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one(0.135 g, 0.326 mmol, 70%) as a light orange waxy solid: IR (CH₂Cl₂)2918, 2200, 1629, 1596, 1425, 1309, 1224, 1144, 1120, 1027, 809 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.58 (d, J=8.4 Hz, 1H), 7.27-7.23 (m, 3H), 6.69(dd, J=3.6, 0.8 Hz, 1H), 3.91 (app t, J=4.9 Hz, 2H), 3.81 (app t, J=5.0Hz, 2H), 2.98 (app t, J=5.0 Hz, 2H), 2.91 (app t, J=5.0 Hz, 2H), 2.49(d, J=0.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.2, 152.7, 152.6,145.5, 138.8, 135.7, 128.5 (q, J_(CF)=5.4 Hz), 125.9, 125.8 (q,J_(CF)=29.3 Hz), 125.6, 124.7, 123.6 (q, J_(CF)=273.0 Hz), 117.4, 85.4,84.5, 53.6, 52.8, 47.3, 41.7, 15.5; ¹⁹F NMR (376 MHz, CDCl₃) δ −60.3 (s,3 F); HRMS (ESI) m/z calcd for C₁₉H₁₇ClF₃N₂OS ([M+H]⁺) 413.0697, found413.0693.

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(5-methylthiophen-2-yl)cyclopropyl)methanone.A solution of1-(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-yn-1-one(0.112 g, 0.271 mmol) in EtOAc (2.7 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0289 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes,product eluted at 20% EtOAc/hexanes) to give(Z)-1-(4-(5-chloro-2-(trifluoromethyl)-phenyl)piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one(0.0655 g, 0.158 mmol) as a colorless foam.

A solution of CrCl₂ (0.116 g, 0.947 mmol) and(Z)-1-(4-(5-chloro-2-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(5-methylthiophen-2-yl)prop-2-en-1-one(0.0655 g, 0.158 mmol) in dry degassed THF (1.6 mL) was sparged with Arfor 5 min and treated with CH₂ICl (0.091 mL, 0.789 mmol) at rt, heatedfor 2 days at 80° C., cooled to rt, diluted with EtOAc (50 mL), andwashed with 1 M aqueous HCl (3×20 mL). The organic layer was dried(MgSO₄), filtered and concentrated under reduced pressure. The cruderesidue was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, 100% hexanes to 30% EtOAc/hexanes, product eluted at20% EtOAc/hexanes), filtered through basic Al₂O₃ (CH₂Cl₂/EtOAc, 1:1),and concentrated under reduced pressure. The resulting oil wascrystalized from cyclohexane (˜0.5 mL at rt), the crystals were washedwith hexanes and dried under high vacuum to give(4-(5-chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)((1RS,2SR)-2-(5-methylthiophen-2-yl)cyclopropyl)methanone(0.0313 g, 0.0730 mmol, 27% (2 steps) (100% purity by ELSD)) as acolorless solid: Mp 84.5-86.8° C.; IR (CH₂Cl₂) 3007, 2920, 1642, 1595,1464, 1435, 1405, 1308, 1144, 1120, 1031, 825, 803 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7.54 (d, J=8.5 Hz, 1H), 7.21 (dd, J=8.5, 1.5 Hz, 1H), 7.03(d, J=1.5 Hz, 1H), 6.61 (dd, J=3.4, 1.0 Hz, 1H), 6.59 (d, J=3.4 Hz, 1H),4.08 (d, J=13.0 Hz, 1H), 3.87 (d, J=13.0 Hz, 1H), 3.57 (ddd, J=13.0,9.4, 3.0 Hz, 1H), 3.23 (ddd, J=13.0, 9.6, 3.0 Hz, 1H), 2.78 (tt, J=9.6,4.7 Hz, 2H), 2.52 (td, J=8.8, 6.8 Hz, 1H), 2.46-2.40 (m, 4H), 2.31-2.25(m, 1H), 2.16 (ddd, J=8.8, 8.2, 6.0 Hz, 1H), 1.77 (q, J=6.0 Hz, 1H),1.39 (td, J=8.6, 6.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.1, 153.2,138.6, 138.5, 137.4, 128.4 (q, J_(CF)=5.4 Hz), 126.0 (q, J_(CF)=28.2Hz), 125.5, 125.1, 124.8, 124.0, 123.6 (q, J_(CF)=273.0 Hz), 53.6, 53.2,45.7, 42.4, 24.4, 19.4, 15.3, 12.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −60.4 (s,3 F); HRMS (ESI) m/z calcd for C₂₀H₂₁ClF₃N₂OS ([M+H]⁺) 429.1010, found429.1006.

3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-yn-1-one.A solution of 3-(3,5-bis(trifluoromethyl)phenyl)propiolic acid (0.250 g,0.886 mmol) and 1-(5-chloro-2-methylphenyl)piperazine hydrochloride(0.263 g, 1.06 mmol) in CH₂Cl₂ (9.0 mL) cooled to 0° C. was treated Et₃N(0.5 mL, 3.54 mmol). The cooled solution was treated with T3P (50%solution in EtOAc) (1.0 mL, 1.33 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min and allowed to warm to rt overnight. Thereaction was diluted with EtOAc (40 mL) and washed with H₂O (20 mL),satd. aqueous NaHCO₃ (20 mL), dried (MgSO₄), filtered, and concentratedunder reduced pressure. The crude material was purified by automatedchromatography on SiO₂ (4 g column, gradient hexanes to EtOAc), to givethe product (0.280 g, 0.590 mmol, 67%) as a pale yellow solid: Mp129.7-132.4° C.; IR (CH₂Cl₂) 2927, 2221, 1638, 1432, 1381, 1279, 1180,1137, 1044, 900, 684 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 2H), 7.92(s, 1H), 7.13 (dd, J=8.4, 0.4 Hz, 1H), 7.01 (dd, J=8.4, 2.0 Hz, 1H),6.96 (d, J=2.0 Hz, 1H), 3.97 (t, J=5.0 Hz, 2H), 3.85 (t, J=5.0 Hz, 2H),3.00 (t, J=5.0 Hz, 2H), 2.91 (t, J=5.0 Hz, 2H), 2.30 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 152.0, 151.6, 132.3 (q, J=34.1 Hz), 132.2, 131.9,131.0, 123.9, 123.5 (q, J=3.6 Hz), 122.8, 122.6 (q, J=273.1 Hz), 119.8,87.0, 83.5, 51.9, 51.3, 47.5, 42.1, 17.4; ¹⁹F NMR (376 MHz, CDCl₃) δ−63.2 (s, 6 F); HRMS (ESI) m/z calcd for C₂₂H₁₈ClF₆N₂O ([M+H]⁺)475.1006, found 475.1004.

((1RS,2SR)-2-(3,5-Bis(trifluoromethyl)phenyl)cyclopropyl)(4-(5-chloro-2-methylphenyl)piperazin-1-yl)methanone.A solution of3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-yn-1-one(0.280 g, 0.590 mmol) in EtOAc (6 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0628 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, hexanes to 40% EtOAc/hexanes, pdteluted at 30% EtOAc/hexanes) to give(Z)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-en-1-one(0.0710 g, 0.149 mmol) as a pale yellow oil.

A solution of CrCl₂ (0.110 g, 0.893 mmol) and(Z)-3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-en-1-one(0.0710 g, 0.149 mmol) in dry degassed THF (1.5 mL) was sparged with Arfor 5 min and treated with CH₂ICl (0.086 mL, 0.744 mmol) at rt, furthersparged for 2 min, heated for 20 h at 80° C., cooled to rt, diluted withEtOAc (50 mL), and washed with 1 M aqueous HCl (3×20 mL). The organiclayer was dried (MgSO₄), filtered and concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 40%EtOAc:hexanes), filtered through basic Al₂O₃ (CH₂Cl₂/EtOAc, 1:1),recrystallized from cyclohexane, and dried under high vacuum to give((1RS,2SR)-2-(3,5-bis(trifluoromethyl)phenyl)cyclopropyl)(4-(5-chloro-2-methylphenyl)piperazin-1-yl)methanone(0.0560 g, 0.114 mmol, 19% (2 steps) (100% purity by ELSD)) as a paleyellow oil: IR (CH₂Cl₂) 2820, 1641, 1466, 1277, 1167, 1132, 1036, 899,682 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.65 (s, 2H), 7.07(dd, J=8.4, 0.6 Hz, 1H), 6.97 (dd, J=8.4, 2.0 Hz, 1H), 6.73 (d, J=2.0Hz, 1H), 3.81-3.64 (m, 3H), 3.35 (ddd, J=12.5, 8.8, 3.1 Hz, 1H), 2.86(dt, J=11.4, 4.1 Hz, 1H), 2.76 (dt, J=11.9, 4.0 Hz, 1H), 2.59 (td,J=8.4, 6.8 Hz, 1H), 2.38-2.27 (m, 3H), 2.21 (s, 3H), 1.96 (dt, J=6.8,5.6 Hz, 1H), 1.47 (td, J=8.4, 5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ166.4, 151.6, 140.4, 132.0, 131.8, 131.4 (q, J_(CF)=33.1 Hz), 130.9,128.3 (q, J_(CF)=1.1 Hz), 123.7, 123.3 (q, J_(CF)=272.7 Hz), 120.4 (q,J_(CF)=3.8 Hz), 119.6, 51.8, 51.6, 45.6, 42.3, 23.8, 23.4, 17.3, 11.3;¹⁹F NMR (376 MHz, CDCl₃) δ −62.7 (s, 6 F); HRMS (ESI) m/z calcd forC₂₃H₂₂ClF₆N₂O ([M+H]⁺) 491.1319, found 491.1312.

3-(4-Chloro-2-fluorophenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-yn-1-one.A solution of 3-(4-chloro-2-fluorophenyl)propiolic acid (0.190 g, 0.957mmol) and 1-(5-chloro-2-methylphenyl)-piperazine hydrochloride (0.284 g,1.15 mmol) in CH₂Cl₂ (9.6 mL) cooled to 0° C. was treated with Et₃N(0.53 mL, 3.83 mmol). The cooled solution was treated with T3P (50%solution in EtOAc) (1.0 mL, 1.44 mmol) dropwise and the reaction wasstirred at 0° C. for 30 min, warmed to rt overnight, diluted with EtOAc(40 mL) and washed with H₂O (20 mL), satd. aqueous NaHCO₃ (20 mL), dried(MgSO₄), filtered, and concentrated under reduced pressure. The cruderesidue was purified by automated chromatography on SiO₂ (4 g column,liquid load CH₂Cl₂, gradient 100% hexanes to 100% EtOAc) to give3-(4-chloro-2-fluorophenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-yn-1-one(0.302 g, 0.772 mmol, 81%) as a pale yellow solid: Mp 135.1-137.3° C.;IR (CH₂Cl₂) 2917, 2820, 2219, 1632, 1489, 1431, 1291, 1224, 1039, 898,819 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (dd, J=8.8, 8.0 Hz, 1H), 7.17(t, J=2.0 Hz, 1H), 7.15 (q, J=2.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.98(dd, J=8.0, 2.0 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 3.97 (t, J=5.0 Hz, 2H),3.83 (t, J=5.0 Hz, 2H), 2.96 (t, J=5.0 Hz, 2H), 2.88 (t, J=5.0 Hz, 2H),2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.0 (d, J_(CF)=257.4 Hz),152.5, 151.6, 137.4 (d, J_(CF)=10.1 Hz), 134.7 (d, J_(CF)=1.4 Hz), 131.9(d, J_(CF)=25.0 Hz), 130.9, 125.0 (d, J_(CF)=3.7 Hz), 123.7, 119.8,116.8, 116.6, 107.9 (d, J_(CF)=15.9 Hz), 86.6 (d, J_(CF)=3.6 Hz), 83.0,51.8, 51.2, 47.3, 41.9, 17.4; ¹⁹F NMR (376 MHz, CDCl₃) δ −105.8 (s, 1F); HRMS (ESI) m/z calcd for C₂₀H₁₈Cl₂FN₂O ([M+H]⁺) 391.0775, found391.0781.

((1RS,2SR)-2-(4-Chloro-2-fluorophenyl)cyclopropyl)(4-(5-chloro-2-methylphenyl)piperazin-1-yl)methanoneA solution of3-(4-chloro-2-fluorophenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-yn-1-one(0.300 g, 0.767 mmol) in EtOAc (7.8 mL) was treated with Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0816 g, equivalent to 5 mol %Pd). The reaction was placed under a balloon of H₂ (3 vacuum/backfillcycles) and stirred at rt for 3 d, filtered through Celite, washed(EtOAc), and the combined filtrates were concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 40% EtOAc/hexanes,pdt eluted at 30% EtOAc/hexanes) to give(Z)-3-(4-chloro-2-fluorophenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-en-1-one(0.138 g, 0.351 mmol, 46%) as a pale yellow oil.

A solution of CrCl₂ (0.259 g, 2.11 mmol) and(Z)-3-(4-chloro-2-fluorophenyl)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)prop-2-en-1-one(0.138 g, 0.351 mmol) in dry degassed THF (3.5 mL) was sparged with Arfor 5 min and treated with CH₂ICl (0.20 mL, 1.75 mmol) at rt, furthersparged for 5 min, heated for 20 h at 80° C., cooled to rt, diluted withEtOAc (50 mL) and washed with 1 M aqueous HCl (3×20 mL). The organiclayer was dried (MgSO₄), filtered, and concentrated under reducedpressure. The crude residue was purified by automated chromatography onSiO₂ (4 g column, liquid load CH₂Cl₂, 100% hexanes to 40%EtOAc/hexanes), filtered through basic Al₂O₃ (1:1 CH₂Cl₂/EtOAc) anddried under high vacuum to give((1RS,2SR)-2-(4-chloro-2-fluorophenyl)cyclopropyl)(4-(5-chloro-2-methylphenyl)piperazin-1-yl)methanone(0.0930 g, 0.228 mmol, 65% (100% purity by ELSD)) as a colorless solid:Mp 100.2-103.0° C.; IR (CH₂Cl₂) 2950, 2819, 1638, 1490, 1435, 1225,1034, 899, 818, 731 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.09-7.03 (m, 4H),6.97 (dd, J=8.0, 2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 3.81-3.66 (m, 3H),3.38 (ddd, J=12.4, 8.0, 3.4 Hz, 1H), 2.91-2.86 (m, 1H), 2.77-2.72 (m,1H), 2.58 (qd, J=8.4, 0.8 Hz, 1H), 2.50 (ddd, J=11.2, 8.0, 2.8 Hz, 1H),2.40 (ddd, J=11.2, 8.0, 2.8 Hz, 1H), 2.29 (ddd, J=9.2, 8.0, 5.6 Hz, 1H),2.23 (s, 3H), 1.90 (dt, J=6.8, 5.6 Hz, 1H), 1.34 (td, J=8.4, 5.6 Hz,1H); ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 161.9 (d, J_(CF)=247.9 Hz),151.9, 132.8 (d, J_(CF)=10.5 Hz), 132.0, 131.8, 130.9, 129.8 (d,J_(CF)=4.5 Hz), 124.2 (d, J_(CF)=3.4 Hz), 123.5, 123.1 (d, J_(CF)=14.3Hz), 119.6, 115.4 (d, J_(CF)=25.3 Hz), 51.8, 51.6, 45.6, 42.2, 22.2,17.4, 17.4, 9.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −116.4 (s, 1 F); HRMS (ESI)m/z calcd for C₂₁H₂₂Cl₂FN₂O ([M+H]⁺) 407.1088, found 407.1089.

1-(5-Chloro-2-methylphenyl)-4-(((1S,2R)-2-(4-fluorophenyl)cyclopropyl)methyl)piperazine(JKJ741.047) A solution of(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1S,2R)-2-(4-fluorophenyl)-cyclopropyl)methanone(0.0372 g, 0.0998 mmol) in THF (0.4 mL) was treated with BH₃DMS (1Msolution in THF, 0.4 mL, 0.400 mmol) under Ar and the reaction washeated at reflux for overnight. The reaction was cooled to 0° C. andquenched by the addition of 1M NaOH and stirred for 20 min at 0° C.until all of the bubbling subsided. The reaction was extracted withEtOAc (3×20 mL), and the combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo. The crude material was stirred in 1MHCl overnight at rt. The resulting solution was made basic with 1M NaOHand extracted with EtOAc (3×10 mL). The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. The crude residuewas purified by automated chromatography on SiO₂ (4 g column, hexanes toEtOAc; pdt eluted at 30% EtOAc/hexanes) to afford the product (0.0157 g,0.0437 mmol, 44%) as a pale yellow oil: IR (CH₂Cl₂) 2927, 2819, 1591,1510, 1489, 1224, 1095, 835 cm⁻¹; ¹H NMR (600 MHz, acetone-d6) δ7.32-7.29 (m, 2H), 7.14 (d, J=8.0 Hz, 1H), 7.06-7.02 (m, 2H), 6.98 (d,J=2.1 Hz, 1H), 6.95 (dd, J=8.0, 2.2 Hz, 1H), 2.85 (bs, 4H), 2.46 (bs,4H), 2.26 (dd, J=12.7, 6.2 Hz, 1H), 2.20 (q, J=8.0 Hz, 4H), 1.93 (dd,J=12.7, 7.1 Hz, 1H), 1.35-1.29 (m, 2H), 1.09 (td, J=8.4, 5.4 Hz, 1H),0.84 (q, J=5.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 162.1 (d, J=242.0Hz), 154.0, 135.9 (d, J=3.1 Hz), 132.9, 132.1, 131.8, 131.6 (d, J=8.0Hz), 123.4, 119.9, 115.3 (d, J=21.1 Hz), 58.3, 54.2, 52.4, 20.4, 17.6,17.1 10.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −119.1 (s, 1 F); HRMS (ESI) m/zcalcd for C₂₁H₂₅ClFN₂ ([M+H]⁺) 359.1685, found 359.1682. [α]¹⁹ _(D)+30.7(c 0.48, MeOH).

tert-Butyl4-(3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)propioloyl)piperazine-1-carboxylate(JKJ759.024). A solution of3-(4-(pentafluoro-└⁶-sulfanyl)phenyl)propiolic acid (0.400 g, 1.47 mmol)and N-boc-piperazine (0.328 g, 1.76 mmol) in CH₂Cl₂ (15 mL) at 0° C. wastreated Et₃N (0.62 mL, 4.41 mmol). The cooled solution was treated withT3P (50% solution in EtOAc) (1.6 mL, 2.20 mmol) dropwise and thereaction was stirred at 0° C. for 30 min and allowed to warm to rtovernight. The reaction was diluted with EtOAc (50 mL) and washed withwater (20 mL), satd. aqueous NaHCO₃ (20 mL), dried (MgSO₄), filtered,and concentrated in vacuo. The crude material was purified bychromatography on SiO₂ (1:1 hexanes/EtOAc), to give tert-butyl4-(3-(4-(pentafluoro-λ6-sulfaneyl)phenyl)propioloyl)piperazine-1-carboxylate(0.457 g, 1.04 mmol, 71%) as a tan solid: Mp 192.4-195.0° C.; IR(CH₂Cl₂) 2981, 1697, 1635, 1419, 1255, 1239, 1167, 841 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 7 7.76 (dt, J=9.0, 2.0 Hz, 2H), 7.63 (d, J=9.0 Hz, 2H),3.79-3.76 (m, 2H), 3.67 (t, J=4.8 Hz, 2H), 3.54-3.51 (m, 2H), 3.46 (t,J=4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 154.4 (quint, J=40.0 Hz),152.4, 132.5, 126.3 (t, J=4.7 Hz), 123.9, 99.9, 88.4, 83.0, 80.6, 46.9,43.3, 41.5, 28.3; ¹⁹F NMR (376 MHz, CDCl₃) δ 83.0 (t, J=150.5 Hz, 1 F),62.4 (d, J=150.2 Hz, 4 F).; HRMS (ESI) m/z calcd for C₁₈H₂₂F₅N₂O₂S([M+H]⁺) 441.1266, found 441.1264.

tert-Butyl4-((1RS,2SR)-2-(4-(pentafluoro-λ6-sulfaneyl)phenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate(JKJ759.031/035). A solution of tert-butyl4-(3-(4-(pentafluorosulfanyl)phenyl)propioloyl)-piperazine-1-carboxylate(0.420 g, 0.954 mmol) in EtOAc (10 mL) at rt was treated with quinoline(0.56 mL, 4.77 mmol) and 5% Pd/BaSO₄ (0.0203 g, 0.0096 mmol, 1 mol %based on Pd) and the reaction was stirred under an atmosphere of H₂ (3×backfill cycles) for 4 h. Analysis by TLC (1:1 H:EA) indicated that thestarting material had been mostly consumed. The reaction was filtered(eluting with EtOAc), and the filtrate was washed with 1M HCl (3×25 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residuewas purified by chromatography on SiO₂ (1:1 hexanes/EtOAc to EtOAc) toafford the product (0.408 g, 0.922 mmol) as a colorless solid. Thissolid was carried on to the cyclopropanation 759.035.

A solution of CrCl₂ (0.667 g, 5.43 mmol) and (Z)-tert-butyl4-(3-(4-(pentafluorosulfanyl)phenyl)-acryloyl)piperazine-1-carboxylate(0.400 g, 0.904 mmol) in anhydrous THF (9 mL) and the mixture wassparged with Ar for 15 min and added CH₂ICl (0.52 mL, 4.52 mmol) at rtand under Ar atmosphere. The reaction mixture was stirred for 24 h at80° C., cooled to rt, diluted with EtOAc (80 mL) and washed with 1Maqueous HCl (3×20 mL). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The crude material was purified by chromatographyon SiO₂ (EtOAc) to afford a the product as a clear oil. The product wasfiltered through basic Al₂O₃ (eluting with EtOAc) concentrated to affordthe product (0.0920 g, 0.202 mmol, 21% (2 steps)) as a colorless solid:Mp 125.3-128.5° C.; IR (neat) 2980, 1679, 1635, 1429, 1364, 1239, 1171,1030, 829 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J=8.6 Hz, 2H), 7.22(d, J=8.6 Hz, 2H), 3.55-3.48 (m, 4H), 3.40-3.35 (m, 1H), 3.26-3.20 (m,1H), 2.85-2.75 (m, 2H), 2.48 (q, J=8.8 Hz, 1H), 2.24 (td, J=8.8, 6.0 Hz,1H), 1.89 (q, J=6.0 Hz, 1H), 1.46-1.38 (m, 10H); ¹³C NMR (100 MHz,CDCl₃) δ 166.7, 154.4, 152.1 (quint, J_(CF)=17.3 Hz), 141.6, 127.8,125.6 (quint, J_(CF)=4.6 Hz), 80.3, 45.0, 43.2, 41.6, 28.3, 24.3, 23.711.2; ¹⁹F NMR (376 MHz, CDCl₃) δ 84.9 (quint, J=150.2 Hz, 1 F), 63.1 (d,J=150.0 Hz, 4 F).; HRMS (ESI) m/z calcd for C₁₉H₂₅F₅N₂O₃SNa ([M+Na]⁺)479.1398, found 479.1395.

tert-Butyl4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazine-1-carboxylate(JKJ759.025). A solution of 3-(4-trifluoromethylphenyl)propiolic acid(0.500 g, 2.33 mmol) and N-Boc-pipreazine (0.522 g, 2.80 mmol) in CH₂Cl₂(23 mL) at 0° C. was treated Et₃N (1.0 mL, 7.00 mmol). The cooledsolution was treated with T3P (50% solution in EtOAc) (2.5 mL, 3.50mmol) dropwise and the reaction was stirred at 0° C. for 30 min andallowed to warm to rt overnight. The reaction was diluted with EtOAc(100 mL) and washed with water (20 mL), satd. aqueous NaHCO₃ (20 mL),dried (MgSO₄), filtered, and concentrated in vacuo. The crude materialwas purified by chromatography on SiO₂ (1:1 hexanes/EtOAc), to give theproduct (0.841 g, 2.20 mmol, 94%) as a colorless solid: Mp 174.2-175.9°C.; IR (CH₂Cl₂) 2981, 2230, 1678, 1622, 1425, 1321, 1162, 1123, 1064,837 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, J=8.8 Hz, 2H), 7.63 (d,J=8.8 Hz, 2H), 3.80-3.77 (m, 2H), 3.66 (t, J=5.0 Hz, 2H), 3.54-3.51 (m,2H), 3.46 (t, J=5.0 Hz, 2H), 1.47 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ154.4, 152.6, 132.6, 131.8 (q, J_(CF)=32.8 Hz), 125.5 (q, J_(CF)=3.9Hz), 124.0, 123.6 (q, J_(CF)=272.7 Hz), 89.2, 82.5, 80.5, 46.8, 41.5,28.3; ¹⁹F NMR (376 MHz, CDCl₃) δ −63.1 (s, 3 F); HRMS (ESI) m/z calcdfor C₁₉H₂₁F₃N₂O₃ ([M+H]⁺) 383.1577, found 383.1576.

tert-Butyl4-((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate(JKJ759.043). A solution of tert-butyl4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazine-1-carboxylate(0.840 g, 2.20 mmol) in EtOAc (22 mL) at rt was treated with quinoline(1.3 mL, 11.0 mmol) and 5% Pd/BaSO₄ (0.0468 g, 0.0220 mmol, 1 mol %based on Pd) and the reaction was stirred under an atmosphere of H₂ (3×backfill cycles) for 2 h. Analysis by TLC (1:1 H:EA) indicated that thestarting material had been mostly consumed. The reaction was filtered(eluting with EtOAc), and the filtrate was washed with 1M HCl (3×25 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. The crude residuewas purified by chromatography on SiO₂ (1:1 hexanes/EtOAc to EtOAc) toafford the product (0.718 g, 1.87 mmol, 85%) as a colorless solid.

A solution of CrCl₂ (1.38 g, 11.2 mmol) and tert-butyl(Z)-4-(3-(4-(trifluoromethyl)phenyl)-acryloyl)piperazine-1-carboxylate(0.718 g, 1.87 mmol) in dry degassed THF (19 mL) (previously spargedwith Ar for 15 min) and treated with CH₂ICl (1.08 mL, 9.34 mmol) andsparged with Ar for 2 min. The reaction mixture was stirred for 24 h at80° C. under an atmosphere of Ar, cooled to rt, diluted with EtOAc (80mL), and washed with 1 M aqueous HCl (3×20 mL). The organic layer wasdried (MgSO₄), filtered and concentrated in vacuo. The crude materialwas purified by chromatography on SiO₂ (EtOAc) to afford the product asa colorless oil. The product was filtered through basic Al₂O₃ (elutingwith EtOAc) concentrated to give tert-butyl4-((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazine-1-carboxylate(0.194 g, 0.487 mmol, 26%) as a colorless solid: Mp 108.6-111.9° C.; IR(CH₂Cl₂) 2978, 1693, 1641, 1417, 1324, 1236, 1162, 1116, 1069, 1017,997, 844 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J=8.4 Hz, 2H), 7.24(d, J=8.4 Hz, 2H), 3.59-3.54 (m, 1H), 3.51-3.36 (m, 4H), 3.23-3.16 (m,1H), 2.82-2.76 (m, 1H), 2.71-2.66 (m, 1H), 2.50 (q, J=8.8 Hz, 1H), 2.23(td, J=8.8, 6.0 Hz, 1H), 1.90 (q, J=6.0 Hz, 1H), 1.46-1.37 (m, 10H); ¹³CNMR (100 MHz, CDCl₃) δ 166.9, 154.4, 141.6, 128.7 (q, J=32.4 Hz), 127.9,125.0 (q, J=3.9 Hz), 124.1 (q, J=272.0 Hz), 80.3, 45.0, 41.6, 28.3,24.3, 24.0, 11.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.4 (s, 3 F); HRMS (ESI)m/z calcd for C₂₀H₂₆F₃N₂O₃ ([M+H]⁺) 399.1890, found 399.1888.

Piperazin-1-yl((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(JKJ759.045). A solution of tert-butyl4-(2-(4-(trifluoromethyl)phenyl)cyclopropanecarbonyl)piperazine-1-carboxylate759.043 (0.169 g, 0.424 mmol) in THF (0.4 mL) was treated with 4M HCl indioxane (0.5 mL, 2.12 mmol) was added and the reaction was stirred at rtfor overnight. The soln was diluted with hexanes (20 mL) and theresulting precipitate was filtered and washed with additional hexanesand Et₂O. The product was dried under high vacuum to afford the product(0.141 g, 0.421 mmol, 99%) as a colorless solid.

(4-((5-Chloro-2-fluorophenyl)sulfonyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone(JKJ759.047). A solution ofpiperazin-1-yl((1RS,2SR)-2-(4-(trifluoromethyl)-phenyl)cyclopropyl)methanonehydrochloride (0.0610 g, 0.182 mmol) and5-chloro-2-fluorobenzene-1-sulfonyl chloride (0.0500 g, 0.219 mmol) inCH₂Cl₂ (2.0 mL) at 0° C. was treated with Et₃N (1.0 mL, 7.00 mmol),stirred at 0° C. for 30 min, warmed to rt overnight, and concentratedunder reduced pressure. The crude material was purified bychromatography on SiO₂ (EtOAc), to give the product (0.0834 g, 0.170mmol, 93% (100% purity by ELSD)) as a colorless solid: Mp 139.7-142.3°C.; IR (CH₂Cl₂) 3095, 2859, 1642, 1469 1324, 1163, 1113, 1069, 939, 844,736 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.73 (dd, J=5.6, 2.6 Hz, 1H), 7.53(ddd, J=8.8, 4.0, 2.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4Hz, 2H), 7.13 (t, J=8.8 Hz, 1H), 3.86 (bd, J=13.2 Hz, 1H), 3.72 (bd,J=13.2 Hz, 1H), 3.51 (ddd, J=13.2, 9.2, 2.8 Hz, 1H), 3.38 (bd, J=13.2Hz, 1H), 3.26-3.14 (m, 2H), 2.49 (q, J=8.8 Hz, 1H), 2.35-2.27 (bq,J=11.6 Hz, 2H), 2.19 (ddd, J=9.2, 8.8, 6.0 Hz, 1H), 1.86 (q, J=6.0 Hz,1H), 1.39 (td, J=8.8, 5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 166.6,157.1 (d, J=255.5 Hz), 141.4, 135.1 (d, J=8.6 Hz), 130.5, 130.0 (d,J=3.6 Hz), 128.5 (q, J=32.5 Hz), 127.7, 126.3 (d, J=16.4 Hz), 124.8 (q,J=3.8 Hz), 124.1 (q, J=271.6 Hz), 118.7 (d, J=23.8 Hz), 46.0, 45.4,44.9, 41.3, 24.3, 23.9, 10.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.2 (s, 3 F),−111.2 (s, 1 F); HRMS (ESI) m/z calcd for C₂₁H₂₀F₄N₂O₃SCl ([M+H]⁺)491.0814, found 491.0812.

(4-(5-Chloro-2-fluorobenzoyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanone(JKJ759.046). A solution ofpiperazin-1-yl((1RS,2SR)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanonehydrochloride (0.0800 g, 0.239 mmol) and 5-chloro-2-fluorobenzoic acid(0.0501 g, 0.287 mmol) in CH₂Cl₂ (2.5 mL) cooled to 0° C. was treatedwith Et₃N (0.13 mL, 0.956 mmol). The cooled solution was treated withT3P (50% solution in EtOAc) (0.25 mL, 0.358 mmol) dropwise and thereaction was stirred at 0° C. for 30 min, warmed to rt overnight,diluted with EtOAc (50 mL), and washed with water (20 mL), satd. AqueousNaHCO₃ (20 mL), dried (MgSO₄), filtered, and concentrated under reducedpressure. The crude residue was purified by chromatography on SiO₂(EtOAc), to give(4-(5-chloro-2-fluorobenzoyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0982 g, 0.216 mmol, 90% (100% purity by ELSD) as a colorless solid:Mp 143.2-145.9° C.; IR (CH₂Cl₂) 3010, 2865, 1635, 1432, 1324, 1113,1068, 1009, 844, 734 cm⁻¹; ¹H NMR (400 MHz, CDCl₃, 50° C. rotomers) δ7.50 (d, J=8.0 Hz, 2H), 7.36-7.24 (m, 4H), 7.01 (t, J=8.8 Hz, 1H), 3.90(bs, 1H), 3.60 (bs, 3H), 3.21 (bs, 2H), 2.98 (bs, 1H), 2.79 (bs, 1H),2.51 (bs, 1H), 2.23 (bs, 1H), 1.91 (q, J=6.0 Hz, 1H), 1.40 (td, J=8.4,5.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃, 20° C.) δ 167.0, 163.8, 156.4 (d,J=248.1 Hz), 141.5, 131.6 (d, J=8.1 Hz), 130.2, 129.2, 128.8 (q, J=32.7Hz), 127.9, 125.1 (q, J=3.7 Hz), 124.2 (q, J=271.8 Hz), 117.3 (d, J=23.6Hz), 46.7, 44.8, 42.3, 41.9, 24.2, 24.1, 11.0; ¹⁹F NMR (376 MHz, CDCl₃)δ −62.4 (s, 3 F), −117.7 (s, 1 F); HRMS (ESI) m/z calcd forC₂₂H₂₀F₄N₂O₂Cl ([M+H]⁺) 455.1144, found 455.1143.

1-(2-Methyl-5-(trifluoromethyl)phenyl)piperazine hydrochloride. Asolution of Boc-piperazine (2.14 g, 11.5 mmol), KOtBu (2.35 g, 20.9mmol), (racemic)-BINAP (0.671 g, 1.05 mmol), Pd₂(dba)₃ (0.194 g, 0.209mmol) in dry toluene (105 mL) was sparged with Ar for 20 min, treatedwith 2-bromo-1-methyl-4-(trifluoromethyl)benzene (2.50 g, 10.5 mmol),and the mixture was heated under Ar at 100° C. overnight, cooled to rt,diluted with Et₂O (125 mL), filtered through Celite, washed (Et₂O), andthe combined filtrates were concentrated under reduced pressure. Thecrude residue was purified by chromatography on SiO₂ (hexanes/EtOAc,9:1) to give tert-butyl4-(2-methyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate (2.49 g,7.23 mmol) as an orange oil.

A solution of tert-butyl4-(2-methyl-5-(trifluoromethyl)phenyl)piperazine-1-carboxylate (2.49 g,7.23 mmol) in THF (3.5 mL) was cooled to 0° C. and treated with 4M HClin dioxane (9.0 mL, 36.2 mmol) was added and the reaction was stirred at0° C. for 30 min and then rt for 4 h. The solution was concentratedunder reduced pressure and the tan solid was precipitated in ether,filtered off from the solution, washed with Et₂O, dried under vacuum togive the crude product. The crude material was recrystallized fromEtOH/hexanes (1:1) to give the product (1.71 g, 6.10 mmol, 58% (2steps)) as colorless needles. Mp 296° C. (decomp); IR (CH₂Cl₂) 2939,2799, 2498, 1610, 1418, 1338, 1307, 1153, 1076, 950, 827 cm⁻¹; ¹H NMR(400 MHz, DMSO-d₆) δ 9.44 (bs, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.35 (dd,J=7.9, 1.0 Hz, 1H), 7.25 (d, J=1.0 Hz, 1H), 3.22 (dd, J=6.2, 3.6 Hz,4H), 3.12 (dd, J=6.2, 3.6 Hz, 4H), 2.33 (s, 3H); ¹³C NMR (100 MHz,DMSO-d₆) δ 150.8, 137.2, 131.9, 127.5 (q, J_(CF)=31.6 Hz), 124.2 (q,J_(CF)=272.1 Hz), 120.1 (q, J_(CF)=3.9 Hz), 115.3 (q, J_(CF)=3.8 Hz),47.9, 43.1, 17.7; ¹⁹F NMR (376 MHz, CDCl₃) δ −60.7 (s, 3 F); HRMS (ESI)m/z calcd for C₁₂H₁₆F₃N₂ ([M+H]⁺) 245.1260, found 245.1261.

1-(5-Chloro-2-(trifluoromethyl)phenyl)piperazine hydrochloride. Twoflasks each containing a solution Boc-piperazine (1.58 g, 8.48 mmol),KOtBu (1.73 g, 15.4 mmol), (racemic)-BINAP (0.480 g, 0.771 mmol),Pd₂dba₃ (0.142 g, 0.154 mmol) in toluene (8 mL) was sparged with argonfor 15 min and treated with 2-bromo-4-chloro-1-(trifluoromethyl)benzene(2.00 g, 7.71 mmol), heated under N₂ at 80° C. for 24 h, cooled to rt,combined, diluted with Et₂O (100 mL) and added Celite and filteredthrough Celite, washed (Et₂O), and the combined organic layers wereconcentrated in vacuo. The crude residue was purified by chromatographyon SiO₂ (hexanes/EtOAc, 9:1) to give4-(5-chloro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (3.12 g,8.55 mmol) as an orange oil.

A solution of tert-butyl4-(5-chloro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (3.12 g,8.55 mmol) in THF (8 mL) was treated with 4M HCl in dioxane (10.7 mL,42.8 mmol), stirred at rt overnight, diluted with hexanes (100 mL), andthe resulting precipitate was filtered and washed with additionalhexanes and Et₂O. The crude material was recrystallized at rt(EtOH/hexanes), crystals were collected by vacuum filtration, washed(hexanes) and dried under high vacuum to give1-(5-chloro-2-(trifluoromethyl)phenyl)-piperazine hydrochloride (1.88 g,6.24 mmol, 41% (2 steps)) as tan solid: Mp 272° C. (decomp); IR (neat)2947, 2726, 2480, 1599, 1576, 1307, 1118, 1037, 946, 819 cm⁻¹; ¹H NMR(400 MHz, DMSO-d₆) δ 9.58 (s, 2H), 7.72 (d, J=8.8 Hz, 1H), 7.57 (d,J=1.6 Hz, 1H), 7.46 (dd, J=8.8, 1.6 Hz, 1H), 3.13 (bs, 8H); ¹³C NMR (100MHz, DMSO-d₆) δ 152.2, 138.3, 129.0 (q, J=5.4 Hz), 125.9, 124.7, 124.2(q, J=29.7 Hz), 123.7 (q, J=273.0 Hz), 49.6, 43.1; ¹⁹F NMR (376 MHz,CDCl₃) δ −59.0 (s, 3 F); HRMS (ESI) m/z calcd for C₁₁H₁₃N₂ClF₃ ([M+H]⁺)265.0714, found 265.0712.

4-Bromo-2-(piperazin-1-yl)benzonitrile hydrochloride. A suspension of4-bromo-2-fluorobenzonitrile (2.00 g, 10.0 mmol), 1-boc-piperazine (1.86g, 10.0 mmol), and Et₃N (1.4 mL, 10.0 mmol) in anhydrous MeCN (5.0 mL)was heated to 110° C. for 21 h, cooled to rt, and concentrated underreduced pressure. The crude residue was purified by chromatography onSiO₂ (hexanes/EtOAc, 9:1) to give tert-butyl4-(5-bromo-2-cyanophenyl)piperazine-1-carboxylate (3.03 g, 8.27 mmol) asa yellow oil.

A solution of tert-butyl4-(5-bromo-2-cyanophenyl)piperazine-1-carboxylate (3.03 g, 8.27 mmol) inTHF (4 mL) was cooled to 0° C. and treated with 4M HCl in dioxane (10.3mL, 41.4 mmol), stirred at 0° C. for 30 min, rt for 16 h, diluted withhexanes (200 mL), and the resulting precipitate was collected by vacuumfiltration, washed with hexanes, ether, and dried under high vacuum togive 4-bromo-2-(piperazin-1-yl)benzonitrile hydrochloride (3.82 g, 13.6mmol, 79% (2 steps)) as a colorless solid: Mp 288° C. (decomp); IR(neat) 2901, 2748, 1459, 1129, 1581, 1411, 1241, 1118, 949, 874 cm⁻¹; ¹HNMR (400 MHz, MeOD-d4) δ 7.59 (d, J=8.0 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H),7.37 (dd, J=8.0, 1.6 Hz, 1H), 3.49 (td, J=4.0, 1.2 Hz, 4H), 3.44 (td,J=4.0, 1.2 Hz, 4H); ¹³C NMR (100 MHz, MeOD-d4) δ 156.5, 136.4, 129.9,127.8, 124.2, 118.2, 106.7, 49.6, 44.9; HRMS (ESI) m/z calcd forC₁₁H₁₃N₃Br ([M+H]⁺) 266.0287, found 266.0286.

1-(5-Chloro-2-fluorophenyl)piperazine hydrochloride. Under N₂atmosphere, CuBr (0.471 g, 3.22 mmol), 1,1′-bi-2-naphthol (0.692 g, 2.41mmol) and DMF (8.04 mL) was added to the flame-dried flask. The mixturewas stirred for 10 minutes before the addition of 1-Boc-piperazine (4.49g, 24.1 mmol), K₃PO₄ (7.04 g, 32.2 mmol) and2-bromo-4-chloro-1-fluorobenzene (2.00 mL, 16.1 mmol). The reactionmixture was stirred at 120° C. for 22.0 h. After cooling to roomtemperature, the mixture was diluted with EtOAc (50 mL) and filteredthrough Celite pad. The filtrate was sequentially washed with saturatedaqueous NH₄Cl (50 mL) and brine (50 mL×3). The resulting organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The crude productwas filtered through a short column of SiO₂ (EtOAc/hexanes, 1:15) toyield a mixture of tert-butyl4-(5-chloro-2-fluorophenyl)piperazine-1-carboxylate (1.50 g) as a lightyellow oil. This mixture was used without further purification.

To a solution of the above product (1.50 g) in 1,4-dioxane (11.7 mL),HCl (4 M in 1,4-dioxane, 4.76 mL) was added at 0° C. The mixture wasstirred at RT for 14 h. The thick suspension was diluted with hexanes(50 mL) and the resulting solid was collected by filtration, washed withhexanes and Et₂O, and dried to give the desired compound as a lightyellow solid (0.408 g, 10% over 2 steps). Mp: 173-174° C.; IR (neat):3013, 2956, 2838, 2528, 2484, 2391, 1516, 1478, 1456, 1393, 1269, 1123,1042, 1019 cm⁻¹; ¹H-NMR (500 MHz; DMSO-d6): δ 9.29 (s, 2H), 7.23 (ddd,J=12.5, 8.7, 0.8 Hz, 1H), 7.13 (dd, J=7.7, 2.5 Hz, 1H), 7.08-7.05 (m,1H), 3.30-3.25 (brd, 4H), 3.25-3.18 (brd, 4H); ¹³C-NMR (125 MHz;DMSO-d6): δ 153.5 (d, J=244.6 Hz), 139.8 (d, J=9.9 Hz), 128.6 (d, J=2.9Hz), 122.4 (d, J=8.3 Hz), 119.4 (d, J=3.1 Hz), 117.6 (d, J=22.6 Hz),46.6 (d, J=3.7 Hz), 42.6; ¹⁹F-NMR (471 MHz; DMSO-d6): δ −124.65 (ddd,J=11.4, 7.0, 3.8 Hz, 1 F); HRMS (ESI): m/z calculated for C₁₀H₁₃ClF([M+H]⁺) 215.0746, found 215.0747

1-(4-(5-Chloro-2-fluorophenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one.To a solution of 3-(4-fluorophenyl)propiolic acid (0.200 g, 1.22 mmol)in CH₂Cl₂ (6.09 mL) at 0° C. was added1-(5-chloro-2-fluorophenyl)piperazine hydrochloride (0.367 g, 1.46mmol), and Et₃N (0.432 mL, 3.05 mmol). T₃P (1.29 mL, 1.83 mmol) wasadded dropwise and the reaction was stirred at 0° C. for 30 min andallowed to warm to room temperature for 33 h. The reaction was dilutedwith CH₂Cl₂ (30 mL) and sequentially washed with 1 M HCl (30 mL×2) andsaturated aqueous NaHCO₃ (30 mL×2). The resulting organic phase wasdried (MgSO₄), filtered and concentrated in vacuo. The crude materialwas purified by chromatography on SiO₂ (hexanes/EtOAc, 1:1) to give1-(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(0.296 g, 0.821 mmol, 67%) as a light yellow crystal. Mp: 139-140° C.;IR (neat): 2217, 1629, 1601, 1506, 1498, 1432, 1286, 1244, 1227, 1205,1156, 1039 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.58-7.54 (m, 2H), 7.11-7.05(m, 2H), 7.01-6.89 (m, 3H), 3.99 (t, J=5.1 Hz, 2H), 3.86 (t, J=5.1 Hz,2H), 3.15 (t, J=5.1 Hz, 2H), 3.09 (t, J=5.1 Hz, 2H); ¹³C-NMR (100 MHz;CDCl₃): δ 163.5 (d, J=252.8 Hz), 154.0 (d, J=245.8 Hz), 140.3 (d, J=9.9Hz), 134.6 (d, J=8.8 Hz), 129.5 (d, J=3.3 Hz), 122.8 (d, J=8.1 Hz),119.6 (d, J=2.9 Hz), 117.2 (d, J=22.4 Hz), 116.4 (d, J=3.7 Hz), 116.1(d, J=22.4 Hz), 90.1, 80.7, 50.7 (d, J=3.2 Hz), 50.0 (d, J=3.4 Hz),46.9, 41.4; ¹⁹F-NMR (376 MHz; CDCl₃): δ −107.24 (tt, J=8.1, 5.5 Hz, 1F), −125.19 (ddd, J=11.4, 7.3, 4.6 Hz, 1 F); HRMS (ESI): m/z calculatedfor C₁₉H₁₆ClON₂F₂ ([M+H]⁺) 361.0914, found 361.0912.

(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)(2-(4-fluorophenyl)cyclopropyl)methanone.To a solution of1-(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yn-1-one(0.275 g, 0.763 mmol) in EtOAc (7.63 mL, 0.1 M) was added Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0812 g, 5.0 mol %). Thereaction vessel was placed under vacuum and backfilled with H₂ (balloon,2×) and allowed to stir for 14 h. The reaction mixture was then filteredthrough celite, washed with EtOAc and concentrated in vacuo. The cruderesidue was purified by chromatography on SiO₂ (hexanes/EtOAc, 1:1) toafford(Z)-1-(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one(0.107 g, 39%) as a light yellow oil. ¹H-NMR (300 MHz; CDCl₃): δ 7.38(dd, J=8.6, 5.4 Hz, 2H), 7.03 (t, J=8.6 Hz, 2H), 6.95-6.91 (m, 2H), 6.78(dd, J=7.7, 1.9 Hz, 1H), 6.68 (d, J=12.5 Hz, 1H), 6.05 (d, J=12.5 Hz,1H), 3.83 (t, J=5.1 Hz, 2H), 3.51 (t, J=5.1 Hz, 2H), 3.02 (t, J=5.1 Hz,2H), 2.71 (t, J=5.1 Hz, 2H).

To a solution of anhydrous CrCl₂ (0.169 g, 1.37 mmol) in THF (2.29 mL)that was degassed by sparging with Ar for 30 min followed by theaddition of(Z)-1-(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-en-1-one(83.0 mg, 0.229 mmol) and CH₂ICl (0.132 mL, 1.14 mmol) at RT and underAr atmosphere. The reaction mixture was stirred at 80° C. After stirringfor 14 h, the mixture was cooled to RT and quenched by the addition of1.0 M aqueous HCl (10 mL) and extracted with EtOAc (3×20 mL). Thecombined organic layer was concentrated, then the residue was diluted inEtOAc (3 mL) and the solution was filtered through a plug of basicalumina, and concentrated. The crude material was purified bychromatography on SiO₂ (EtOAc/hexanes, 1:1) to afford(4-(5-chloro-2-fluorophenyl)piperazin-1-yl)(2-(4-fluorophenyl)cyclopropyl)methanoneas a white crystal (67 mg, 78%): Mp: 108-109° C.; IR (neat): 1638, 1606,1512, 1498, 1436, 1230, 1209, 1032 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.12(dd, J=8.5, 5.5 Hz, 2H), 6.97-6.88 (m, 4H), 6.72 (dd, J=7.3, 1.9 Hz,1H), 3.79 (d, J=12.8 Hz, 1H), 3.69 (t, J=17.1 Hz, 2H), 3.39 (t, J=9.5Hz, 1H), 2.99 (t, J=13.9 Hz, 2H), 2.52-2.42 (m, 2H), 2.40-2.34 (m, 1H),2.20-2.15 (m, 1H), 1.84-1.80 (m, 1H), 1.37-1.32 (m, 1H). ¹³C-NMR (125MHz; CDCl₃): δ 167.2 , 161.6 (d, J=245.2 Hz), 154.1 (d, J=246.1 Hz),140.4 (d, J=9.9 Hz), 133.0 (d, J=2.8 Hz), 129.4 (d, J=3.3 Hz), 129.0 (d,J=7.5 Hz), 122.4 (d, J=8.1 Hz), 119.3 (d, J=2.8 Hz), 117.1 (d, J=22.7Hz), 115.0 (d, J=21.2 Hz), 50.6, 50.1, 45.1, 41.7, 23.7, 23.5, 10.6.HRMS (ESI): m/z calculated for C₂₀H₂₀N₂OClF₂ ([M+H]⁺) 377.1227, found377.1221.

Trimethyl((4-(trifluoromethyl)phenyl)ethynyl)silane. A flame-dried flaskunder Ar was added with Pd(PPh)₂Cl₂ (0.496 g, 0.707 mmol), CuI (0.137 g,0.707 mmol), and 4-bromobenzotrifluoride (10.0 mL, 70.7 mmol). The flaskwas purged with Ar before triethylamine (141 mL) and(trimethylsilyl)acetylene (15.0 mL, 106 mmol) were added via syringe andthe solution was sparged with Ar for 10 min. The resulting mixture washeated to 80° C. for 22.5 h. After cooling the reaction to RT, thesolution was filtered through celite, which was washed with EtOAc untilthe washes appeared colorless. The filtrate was concentrated in vacuo.The crude product was purified by chromatography on SiO₂ (hexanes) toafford trimethyl((4-(trifluoromethyl)phenyl)ethynyl)silane (17.1g, >99%) as a light yellow oil: ¹H-NMR (400 MHz; CDCl₃): δ 7.55 (s, 4H),0.26 (s, 9H). The spectra obtained are in agreement with previouslyreported data (Rahaim et al., J. Org. Chem. 2008, 73:2912-2915).

3-(4-(Trifluoromethyl)phenyl)propionic acid. A dried and CO₂ (balloon)infused flask, equipped with a magnetic stirrer and a septum, wascharged with CsF (13.0 g, 84.7 mmol). A solution of((4-trifluoro-phenyl)ethynyl)trimethylsilane (17.1 g, 70.6 mmol) in dryDMSO (141 mL) was added dropwise to a reaction mixture by usingequal-dropping funnel and the reaction was stirred under CO₂ at roomtemperature for 21 h. After that, the reaction mixture was quenched withwater (300 mL) at 0° C. Then the mixture was washed with CH₂Cl₂ (300mL×2) and the resulting water phase was acidified with 1 M aqueous HCl(300 mL). Then the solution was extracted with Et₂O (500 mL×3), dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting solid wascollected during washing it with hexanes. The collecting solid was driedunder reduced pressure to yield 3-(4-(trifluoromethyl)phenyl)propionicacid (14.8 g, 98%) as a light brown solid: ¹H-NMR (400 MHz; DMSO-d₆): δ14.27-13.92 (brs, 1H), 7.88-7.83 (m, 4H). The spectra obtained are inagreement with previously reported data (Cheng et al., Green Chem. 2015,17:1675-1682).

1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one.To a solution of 3-(4-trifluorophenyl)propionic acid(0.20 g, 0.934 mmol)in CH₂Cl₂ (9.34 mL) at 0° C. was added1-(5-chloro-2-methylphenyl)piperazine (0.276 g, 1.12 mmol), and Et₃N(0.530 mL, 3.74 mmol). T₃P (0.991 mL, 1.40 mmol) was added dropwise andthe reaction was stirred at 0° C. for 30 min and allowed to warm to roomtemperature for 18.5 h. The reaction was quenched with saturated aqueousNH₄Cl solution (20 mL) and extracted with CH₂Cl₂ (40 mL×3). The combinedorganic phase was dried (MgSO₄), filtered and concentrated in vacuo. Thecrude material was purified by chromatography on SiO₂ (EtOAc/hexanes,1:4) to afford1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.222 g, 58%) as a light yellow crystal. Mp: 104-106° C.; IR (neat):1633, 1593, 1490, 1431, 1322, 1126 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.67(d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.12 (dd, J=8.1, 0.4 Hz, 1H),7.00 (dd, J=8.1, 2.1 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 3.97 (t, J=5.0 Hz,2H), 3.85 (t, J=5.0 Hz, 2H), 2.98 (t, J=5.0 Hz, 2H), 2.90 (t, J=5.0 Hz,2H), 2.29 (s, 3H). ¹³C-NMR (100 MHz; CDCl₃): δ 152.6, 151.6, 132.6,132.1, 131.7 (q, J=32.9 Hz), 131.0, 125.5 (q, J=3.7 Hz), 124.2, 123.9,123.6 (q, J=273.7 Hz), 119.8, 89.0, 82.73, 51.9, 51.3, 47.4, 42.0, 17.4.¹⁹F-NMR (376 MHz; CDCl₃): δ −63.07 (s, 3 F). HRMS (ESI): m/z calculatedfor C₂₁H₁₉N₂OClF₃ ([M+H]⁺) 407.1133, found 407.1132.

(Z)-1-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one.To a solution of1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.186 g, 0.457 mmol) in EtOAc (4.60 mL, 0.1 M) was added Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0487 g, 5.0 mol %). Thereaction vessel was placed under vacuum and backfilled with H₂ (balloon,2×) and allowed to stir for 18 h. The reaction mixture was then filteredthrough celite, washed with EtOAc and concentrated in vacuo. The crudeproduct was purified by chromatography on SiO₂ (hexanes/EtOAc, 1:1) toafford(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(0.184 g, 98%) as a white crystal. Mp: 109-111° C.; IR (neat): 1621,1594, 1490, 1440, 1325, 1124 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.62 (d,J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.96 (dd,J=8.1, 2.1 Hz, 1H), 6.78 (d, J=2.1 Hz, 1H), 6.74 (d, J=12.6 Hz, 1H),6.21 (d, J=12.6 Hz, 1H), 3.81 (t, J=5.0 Hz, 2H), 3.49 (t, J=5.0 Hz, 2H),2.80 (t, J=5.0 Hz, 2H), 2.51 (t, J=5.0 Hz, 2H), 2.21 (s, 3H). ¹³C-NMR(100 MHz; CDCl₃): δ 166.8, 151.6, 138.9, 132.3, 132.1, 131.9, 131.0,130.5 (q, J=32.2 Hz), 128.7, 125.6 (q, J=3.9 Hz), 125.3, 123.9 (q,J=270.5 Hz), 123.8, 119.7, 51.5, 51.3, 46.6, 41.6, 17.3. ¹⁹F-NMR (376MHz; CDCl₃): δ −62.66 (s, 3 F). HRMS (ESI): m/z calculated forC₂₁H₁₉N₂OClF₃ ([M+H]⁺) 407.1133, found 407.1132.

(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone.To a solution of anhydrous CrCl₂ (0.273 g, 2.16 mmol) in THF (162 mL)that was degassed by sparging with Ar for 30 min followed by theaddition of(Z)-1-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)-3-(4-trifluorophenyl)prop-2-en-1-one(0.147 g, 0.360 mmol) and CH₂ICl (0.134 mL, 1.80 mmol) at roomtemperature and under Ar atmosphere. The reaction mixture was stirred at80° C. After stirring for 17.5 h, the reactions were was cooled to roomtemperature, combined, quenched by the addition of 1.0 M aqueous HCl (10mL) and extracted with EtOAc (3×20 mL). The organic layers werecombined, dried (Na₂SO₄), filtered through a plug of basic alumina andconcentrated in vacuo. The crude material was purified by chromatographyon SiO₂ (EtOAc/hexanes, 1:1) to afford(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(127 mg) as a white solid. Then the product was recrystallized withcyclohexane to afford the target product as a white crystal (89 mg,59%): Mp: 109-110° C.; IR (neat): 1638, 1619, 1593, 1437, 1324, 1116,1069 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.54 (d, J=8.1 Hz, 2H), 7.28 (d,J=8.1 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.1, 2.1 Hz, 1H),6.67 (d, J=2.1 Hz, 1H), 3.82-3.78 (m, 1H), 3.70-3.58 (m, 2H), 3.37-3.31(m, 1H), 2.79-2.69 (m, 2H), 2.51 (q, J=8.0 Hz, 1H), 2.30-2.23 (m, 2H),2.19 (s, 3H), 2.13-2.08 (m, 1H), 1.91 (q, J=6.2 Hz, 1H), 1.45-1.40 (m,1H). ¹³C-NMR (100 MHz; CDCl₃): δ 166.7, 151.7, 141.9, 141.9, 131.9,131.8, 130.9, 128.7 (q, J=32.5 Hz), 127.9, 125.0 (q, J=3.8 Hz), 124.2(q, J=270.0 Hz), 123.7, 119.6, 51.8, 51.5, 45.5, 42.2, 24.5, 24.0, 17.3,11.1. ¹⁹F-NMR (376 MHz; CDCl₃): δ −62.31 (s, 1 F). HRMS (ESI): m/zcalculated for C₂₂H₂₃N₂OClF₃ ([M+H]⁺) 423.1446, found 423.1443.

Racemic(2-(4-fluorophenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%MeOH, 7 mL/min, 220 nM, P=100) to afford(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)-phenyl)cyclopropyl)methanone(retention time; 5.12 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)−150.5 (c 0.51, MeOH); HRMS (ESI): m/z calculated forC₂₂H₂₃N₂OClF₃ ([M+H]⁺) 423.1446, found 423.1449. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 30% MeOH, 220 nM, 7 mL/min;retention time: 5.12 min). ¹H-NMR (400 MHz; CDCl₃): δ 7.54 (d, J=8.1 Hz,2H), 7.28 (d, J=8.1 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.1,2.1 Hz, 1H), 6.67 (d, J=2.1 Hz, 1H), 3.82-3.78 (m, 1H), 3.70-3.58 (m,2H), 3.37-3.31 (m, 1H), 2.79-2.69 (m, 2H), 2.51 (q, J=8.0 Hz, 1H),2.30-2.23 (m, 2H), 2.19 (s, 3H), 2.13-2.08 (m, 1H), 1.91 (q, J=6.2 Hz,1H), 1.45-1.40 (m, 1H).

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone(retention time; 6.43 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)+148.4 (c 0.51, MeOH); HRMS (ESI): m/z calculated forC₂₂H₂₃N₂OClF₃ ([M+H]⁺) 423.1446, found 423.1444. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 30% MeOH, 220 nM, 7 mL/min;retention time: 6.43 min). ¹H-NMR (400 MHz; CDCl₃): δ 7.54 (d, J=8.1 Hz,2H), 7.28 (d, J=8.1 Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.95 (dd, J=8.1,2.1 Hz, 1H), 6.67 (d, J=2.1 Hz, 1H), 3.82-3.78 (m, 1H), 3.70-3.58 (m,2H), 3.37-3.31 (m, 1H), 2.79-2.69 (m, 2H), 2.51 (q, J=8.0 Hz, 1H),2.30-2.23 (m, 2H), 2.19 (s, 3H), 2.13-2.08 (m, 1H), 1.91 (q, J=6.2 Hz,1H), 1.45-1.40 (m, 1H).

3-(4-Fluorophenyl)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)prop-2-yn-1-one.To a solution of 3-(4-fluorophenyl)propionic acid (0.100 g, 0.609 mmol)in CH₂Cl₂ (6.09 mL) at 0° C. was added1-(5-trifluoromethyl-2-methylphenyl)piperazine (0.205 g, 0.731 mmol),and Et₃N (0.259 mL, 1.83 mmol). T₃P (0.646 mL, 0.914 mmol) was addeddropwise and the reaction was stirred at 0° C. for 30 min and allowed towarm to room temperature for 20.5 h. The reaction was diluted withCH₂Cl₂ (40 mL) and washed with 1 M HCl (50 mL). The aqueous phase wasextracted with CH₂Cl₂ (30×2) and combined organic phase was dried(MgSO₄), filtered and concentrated in vacuo. The crude material waspurified by chromatography on SiO₂ (EtOAc/hexanes, 1:4) to afford3-(4-fluorophenyl)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)prop-2-yn-1-one(219 mg, 92%) as a white crystal: Mp: 176-177° C.; IR (neat): 2220,1630, 1600, 1507, 1419, 1310, 1226, 1120 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃):δ 7.56 (dd, J=8.8, 5.3 Hz, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1Hz, 1H), 7.22 (s, 1H), 7.08 (t, J=8.8 Hz, 2H), 4.00 (t, J=5.0 Hz, 2H),3.87 (t, J=5.0 Hz, 2H), 3.03 (t, J=4.9 Hz, 2H), 2.94 (t, J=5.0 Hz, 2H),2.40 (s, 3H). ¹³C-NMR (100 MHz; CDCl₃): δ 163.6 (d, J=252.4 Hz), 153.1,151.0, 136.8, 134.6, 134.5, 131.6, 129.1 (q, J=32.2 Hz), 124.1 (q,J=270.4 Hz), 120.5 (q, J=3.8 Hz,), 116.4 (d, J=3.7 Hz), 116.1 (q, J=3.7Hz), 116.0 (d, J=22.0 Hz), 90.0, 80.8, 80.8, 77.3, 77.0, 76.7, 51.9,51.4, 47.4, 41.9, 18.0. ¹⁹F-NMR (376 MHz; CDCl₃): δ −62.29 (s, 3 F),−107.28-−107.35 (m, 1 F). HRMS (ESI): m/z calculated for C₂₁H₁₉N₂OF₄([M+H]⁺) 391.1428, found 391.1402.

(Z)-3-(4-Fluorophenyl)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)prop-2-en-1-one.To a solution of3-(4-fluorophenyl)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)prop-2-yn-1-one(0.193 g, 0.494 mmol) in EtOAc (4.90 mL, 0.1 M) was added Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0526 g, 5.0 mol %). Thereaction vessel was placed under vacuum and backfilled with H₂ (balloon,2×) and allowed to stir for 18 h. The reaction mixture was then filteredthrough celite, washed with EtOAc and concentrated in vacuo. The cruderesidue was purified by chromatography on SiO₂ (hexanes/EtOAc, 1:1) toafford(Z)-3-(4-fluorophenyl)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)prop-2-en-1-one(0.107 g, 55%) as a light yellow oil: Mp: 176-177° C.; IR (neat): 2917,1640, 1617, 1602, 1508, 1439, 1417, 1338, 1309, 1225, 1162, 1119 cm⁻¹;¹H-NMR (400 MHz; CDCl₃): δ 7.42 (dd, J=8.7, 5.3 Hz, 2H), 7.30-7.25 (m,2H), 7.10-7.06 (m, 3H), 6.71 (d, J=12.5 Hz, 1H), 6.09 (d, J=12.5 Hz,1H), 3.85 (t, J=5.0 Hz, 2H), 3.54 (t, J=5.0 Hz, 2H), 2.87 (t, J=5.0 Hz,2H), 2.58 (t, J=5.0 Hz, 2H), 2.34 (s, 3H); ¹³C-NMR (100 MHz; CDCl₃): δ167.3, 162.7 (d, J=249.4 Hz), 151.0, 136.8, 132.7, 131.6 (d, J=3.6 Hz),131.5, 130.3 (d, J=8.1 Hz), 129.0 (q, J=32.2 Hz), 124.1 (q, J=270.4 Hz),122.7, 122.7, 120.4 (q, J=3.9 Hz), 115.9 (q, J=3.7 Hz), 115.7, 115.6,51.4, 51.3, 46.6, 41.5, 17.9: ¹⁹F-NMR (376 MHz; CDCl₃): δ −62.36 (s, 3F), −112.02-−112.09 (m, 1 F): HRMS (ESI): m/z calculated for C₂₁H₂₁N₂OF₄([M+H]⁺) 393.1585, found 393.1585.

(2-(4-Fluorophenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone.To a solution of anhydrous CrCl₂ (0.172 g, 1.36 mmol) in THF (2.27 mL)that was degassed by sparging with Ar for 10 min followed by theaddition of(Z)-3-(4-fluorophenyl)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)-piperazin-1-yl)prop-2-en-1-one(0.0889 g, 0.227 mmol) and CH₂ICl (0.0842 mL, 1.13 mmol) at roomtemperature and under Ar atmosphere. The reaction mixture was stirred at80° C. After stirring for 13 h, the reactions were was cooled to roomtemperature, combined, quenched by the addition of 1.0 M aqueous HCl (10mL) and extracted with EtOAc (30 mL). The organic layer was sequentiallywashed with 1 M aqueous HCl (30 mL) and saturated aqueous sodiumthiosulfate (30 mL). Then the organic phase was dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was diluted in minimum amount of3:2 mixed solvent of EtOAc and hexanes, and the solution was filteredthrough a plug of basic alumina, and concentrated in vacuo. The crudematerial was purified by chromatography on SiO₂ (EtOAc/hexanes, 3:2) toafford(2-(4-fluorophenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone(0.0878 g, 95%) as a brown oil: IR (neat): 2918, 1637, 1513, 1417, 1337,1307, 1223, 1161, 1118 cm⁻¹; ¹H-NMR (500 MHz; CDCl₃): δ 7.27 (t, J=1.6Hz, 2H), 7.17 (dd, J=8.7, 5.3 Hz, 2H), 7.02-6.98 (m, 3H), 3.90-3.85 (m,1H), 3.78-3.74 (m, 1H), 3.70-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.86-2.77(m, 2H), 2.51-2.46 (m, 1H), 2.33-2.20 (m, 6H), 1.86 (q, J=6.2 Hz, 1H),1.38 (td, J=8.5, 5.5 Hz, 1H): ¹³C-NMR (125 MHz; CDCl₃): δ 167.2, 161.6(d, J=245.2 Hz), 151.1, 136.8, 133.0 (d, J=2.7 Hz), 131.4, 129.0 (d,J=7.9 Hz), 129.0 (q, J=25.5 Hz), 124.1 (q, J=272.0 Hz), 120.3 (q, J=3.7Hz), 115.9 (q, J=3.7 Hz), 115.0, 114.8, 51.7, 51.6, 45.5, 42.2, 23.9,23.4, 17.8, 10.6. ¹⁹F-NMR (471 MHz; CDCl₃): δ −62.36 (s, 1 F),−116.30-−116.41 (m, 1 F); HRMS (ESI): m/z calculated for C₂₂H₂₃N₂OF₄([M+H]⁺) 407.1741, found 407.1732.

Racemic(2-(4-fluorophenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%MeOH, 7 mL/min, 220 nM, P=100) to afford((1S,2R)-2-(4-fluorophenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone(retention time; 4.40 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)−145.6 (c 0.86, MeOH); HRMS (ESI): m/z calculated forC₂₂H₂₃N₂OF₄ ([M+H]⁺) 407.1741, found 407.1741. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 30% MeOH, 220 nM, 7 mL/min;retention time: 4.40 min). ¹H-NMR (500 MHz; CDCl₃): δ 7.27 (t, J=1.6 Hz,2H), 7.17 (dd, J=8.7, 5.3 Hz, 2H), 7.02-6.98 (m, 3H), 3.90-3.85 (m, 1H),3.78-3.74 (m, 1H), 3.70-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.86-2.77 (m,2H), 2.51-2.46 (m, 1H), 2.33-2.20 (m, 6H), 1.86 (q, J=6.2 Hz, 1H), 1.38(td, J=8.5, 5.5 Hz, 1H).

((1R,2S)-2-(4-Fluorophenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone(retention time; 4.74 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)+139.8 (c 1.14, MeOH); HRMS (ESI): m/z calculated forC₂₂H₂₃N₂OF₄ ([M+H]⁺) 407.1741, found 407.1741. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 30% MeOH, 220 nM, 7 mL/min;retention time: 4.74 min). ¹H-NMR (500 MHz; CDCl₃): δ 7.27 (t, J=1.6 Hz,2H), 7.17 (dd, J=8.7, 5.3 Hz, 2H), 7.02-6.98 (m, 3H), 3.90-3.85 (m, 1H),3.78-3.74 (m, 1H), 3.70-3.65 (m, 1H), 3.40-3.35 (m, 1H), 2.86-2.77 (m,2H), 2.51-2.46 (m, 1H), 2.33-2.20 (m, 6H), 1.86 (q, J=6.2 Hz, 1H), 1.38(td, J=8.5, 5.5 Hz, 1H).

1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one.To a solution of 3-(4-trifluorophenyl)propionic acid(0.100 g, 0.467mmol) in CH₂Cl₂ (6.09 mL) at 0° C. was added1-(5-trifluoromethyl-2-methylphenyl)piperazine (0.157 g, 0.560 mmol),and Et₃N (0.199 mL, 1.40 mmol). T₃P (0.495 mL, 0.700 mmol) was addeddropwise and the reaction was stirred at 0° C. for 30 min and allowed towarm to room temperature for 20.5 h. The reaction was diluted withCH₂Cl₂ (40 mL) and washed with 1 M HCl (50 mL). The aqueous phase wasextracted with CH₂Cl₂ (30 mL×2) and combined organic phase was dried(MgSO₄), filtered and concentrated in vacuo. The crude material waspurified by chromatography on SiO₂ (EtOAc/hexanes, 1:4) to afford1-(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(188 mg, 91%) as a white crystal: Mp: 159-160° C.; IR (neat): 2224,1631, 1458, 1431, 1418, 1339, 1321, 1310, 1279, 1165, 1119 cm⁻¹; ¹H-NMR(400 MHz; CDCl₃): δ 7.68 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H), 7.32(d, J=8.3 Hz, 1H), 7.28 (dd, J=8.3, 1.2 Hz, 1H), 7.22 (s, 1H), 4.00 (t,J=5.0 Hz, 2H), 3.88 (t, J=5.0 Hz, 2H), 3.04 (t, J=5.0 Hz, 2H), 2.95 (t,J=5.0 Hz, 2H), 2.40 (s, 3H); ¹³C-NMR (100 MHz; CDCl₃): δ 152.6, 150.9,136.8, 132.6, 131.8 (q, J=32.4 Hz), 131.6, 129.2 (q, J=32.2 Hz), 125.5(q, J=3.7 Hz), 124.1 (q, J=270.5 Hz), 123.6 (q, J=271.1 Hz), 120.6 (q,J=3.8 Hz), 116.1(q, J=3.7 Hz), 89.1, 82.7, 77.4 77.0, 76.7, 51.9, 51.4,47.5, 42.0, 18.0; ¹⁹F-NMR (376 MHz; CDCl₃): δ −62.29 (s, 3 F), −63.09(s, 3 F); HRMS (ESI): m/z calculated for C₂₂H₁₉N₂OF₆ ([M+H]⁺) 441.1396,found 441.1385.

(Z)-1-(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one.To a solution of1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)-phenyl)prop-2-yn-1-one(0.164 g, 0.372 mmol) in EtOAc (3.72 mL, 0.1 M) was added Lindlar'scatalyst (5% Pd on CaCO₃, lead poisoned, 0.0396 g, 5.0 mol %). Thereaction vessel was placed under vacuum and backfilled with H₂ (balloon,2×) and allowed to stir for 18 h. The reaction mixture was then filteredthrough celite, washed with EtOAc and concentrated in vacuo. The cruderesidue was purified by chromatography on SiO₂ (hexanes/EtOAc, 1:1) toafford(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0998 g, 61%) as a light yellow oil: IR (neat): 2978, 1622, 1442,1417, 1327, 1118 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.40 (dd, J=8.7, 5.4Hz, 2H), 7.28-7.23 (m, 2H), 7.05 (t, J=8.7 Hz, 3H), 6.68 (d, J=12.5 Hz,1H), 6.07 (d, J=12.5 Hz, 1H), 3.83 (t, J=4.9 Hz, 2H), 3.52 (t, J=4.9 Hz,2H), 2.85 (d, J=4.9 Hz, 2H), 2.57 (d, J=4.9 Hz, 2H), 2.32 (s, 3H);¹³C-NMR (125 MHz; CDCl₃): δ 166.8, 150.9, 138.8, 136.8, 132.4, 131.5,130.5 (q, J=32.7 Hz), 129.1 (q, J=29.3 Hz), 128.7, 125.6 (q, J=3.7 Hz),125.3, 124.1 (q, J=216.1 Hz), 123.9 (q, J=216.4 Hz), 120.5 (q, J=3.9Hz), 115.9 (q, J=3.6 Hz), 77.3, 77.0, 76.8, 51.4, 51.3, 46.6, 41.6,17.9; ¹⁹F-NMR (376 MHz; CDCl₃): δ −62.41 (s, 3 F), −62.79 (s, 3 F); HRMS(ESI): m/z calculated for C₂₂H₂₁N₂OF₆ ([M+H]⁺) 443.1553, found 443.1551.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanone.To a solution of anhydrous CrCl₂ (0.134 g, 1.06 mmol) in THF (1.80 mL)that was degassed by sparging with Ar for 10 min followed by theaddition of(Z)-1-(4-(2-methyl-5-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(0.0782 g, 0.177 mmol) and CH₂ICl (0.0657 mL, 0.884 mmol) at roomtemperature and under Ar atmosphere. The reaction mixture was stirred at80° C. After stirring for 16.5 h, the reactions were was cooled to roomtemperature, combined, quenched by the addition of 1.0 M aqueous HCl (10mL) and extracted with EtOAc (30 mL). The organic layer was sequentiallywashed with 1 M aqueous HCl (30 mL×2) and saturated aqueous sodiumthiosulfate (30 mL). Then the organic phase was dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was diluted in EtOAc, and thesolution was filtered through a plug of basic alumina, and concentratedin vacuo. The crude material was purified by chromatography on SiO₂(EtOAc/hexanes, 3:2) to afford(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0878 g, 61%) as a white solid: Mp: 99-101° C.; IR (neat): 1639, 1619,1438, 1418, 1325, 1308, 1162, 1114 cm⁻¹; ¹H-NMR (400 MHz; CDCl₃): δ 7.53(d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 2H), 6.94(s, 1H), 3.88-3.82 (m, 1H), 3.73-3.60 (m, 2H), 3.38-3.31 (m, 1H),2.84-2.73 (m, 2H), 2.52 (q, J=7.9 Hz, 1H), 2.31-2.25 (m, 5H), 2.16-2.10(m, 1H), 1.92 (q, J=6.3 Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H); ¹³C-NMR(100 MHz; CDCl₃): δ 166.7, 151.0, 141.9, 141.9, 136.8, 131.4, 129.1 (q,J=31.9 Hz), 128.8 (q, J=32.1 Hz), 127.9, 125.0 (q, J=3.7 Hz), 124.2 (q,J=270.3 Hz), 124.1 (q, J=270.4 Hz), 120.4 (q, J=3.9 Hz), 115.8 (q, J=3.7Hz), 77.4, 77.1, 76.7, 51.8, 51.6, 45.5, 42.2, 24.6, 24.0, 17.8, 11.1;¹⁹F-NMR (376 MHz; CDCl₃): δ −62.46 (s, 3 F), −62.52 (s, 3 F); HRMS(ESI): m/z calculated for C₂₃H₂₃N₂OF₆ ([M+H]⁺) 457.1709, found 457.1709.

Racemic(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%MeOH, 7 mL/min, 220 nM, P=100) to afford(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(retention time; 3.36 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)−139.3 (c 0.77, MeOH); HRMS (ESI): m/z calculated forC₂₃H₂₃N₂OF₆ ([M+H]⁺) 457.1709, found 457.1709. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 30% MeOH, 220 nM, 7 mL/min;retention time: 3.36 min). ¹H-NMR (400 MHz; CDCl₃): δ 7.53 (d, J=8.1 Hz,2H), 7.29 (d, J=8.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 2H), 6.94 (s, 1H),3.88-3.82 (m, 1H), 3.73-3.60 (m, 2H), 3.38-3.31 (m, 1H), 2.84-2.73 (m,2H), 2.52 (q, J=7.9 Hz, 1H), 2.31-2.25 (m, 5H), 2.16-2.10 (m, 1H), 1.92(q, J=6.3 Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H).

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanone(retention time; 3.74 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)+135.7 (c 0.91, MeOH); HRMS (ESI): m/z calculated forC₂₃H₂₃N₂OF₆ ([M+]⁺) 457.1709, found 457.1704. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 30% MeOH, 220 nM, 7 mL/min;retention time: 3.74 min). (400 MHz; CDCl₃): δ 7.53 (d, J=8.1 Hz, 2H),7.29 (d, J=8.1 Hz, 2H), 7.24 (d, J=1.6 Hz, 2H), 6.94 (s, 1H), 3.88-3.82(m, 1H), 3.73-3.60 (m, 2H), 3.38-3.31 (m, 1H), 2.84-2.73 (m, 2H), 2.52(q, J=7.9 Hz, 1H), 2.31-2.25 (m, 5H), 2.16-2.10 (m, 1H), 1.92 (q, J=6.3Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H).

3-Fluoro-2-(4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazin-1-yl)benzonitrile.Under N₂ atmosphere, CuBr (0.717 g, 4.90 mmol), 1,1′-bi-2-naphthol (1.05g, 3.67 mmol) and DMF (12.3 mL) was added to the flame-dried flask. Themixture was stirred for 10 minutes before the addition of1-Boc-piperazine (6.84 g, 36.7 mmol), K₃PO₄ (10.7 g, 49.0 mmol) and2-bromo-3-fluorobenzonitrile (5.00 g, 24.5 mmol). The reaction mixturewas stirred at 120° C. for 22.5 h. After cooling to room temperature,the mixture was diluted with dichloromethane and filtered through Celitepad. The filtrate was concentrated under reduced pressure. The residuewas diluted with Et₂O (100 mL) and the solution was sequentially washedwith saturated aqueous NH₄Cl (100 mL×2) and brine (100 mL×2), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product wasfiltered through a short column of SiO₂ (EtOAc/hexanes, 1:9) to removethe remained piperazine. And the obtained mixture (1.10 g) was usedwithout further purification.

To a solution of the above mixture (1.10 g) in 1,4-dioxane (8.40 mL),HCl (4 M in 1,4-dioxane, 3.60 mL) was added at 0° C. The mixture wasstirred at RT for 12 h. The thick suspension was diluted with hexanes(50 mL) and the resulting solid was collected by filtration, washed withhexanes and Et₂O and dried to give a yellow solid (0.3827 g). Thisproduct was used without further purification.

To a solution of 3-(4-(trifluoromethyl)phenyl)propiolic acid (0.200 g,0.934 mmol) in dry CH₂Cl₂ (12.2 mL) at 0° C. was added the above solid(0.271 g), and Et₃N (0.398 mL, 2.80 mmol). T₃P (0.991 mL, 1.40 mmol) wasadded dropwise and the reaction was stirred at 0° C. for 30 min andallowed to warm to RT for 6.5 h. The reaction was diluted with CH₂Cl₂(40 mL) and washed with 1 M HCl (50 mL). The aqueous phase was extractedwith CH₂Cl₂ (30 mL×2) and combined organic phase was dried (MgSO₄),filtered, and concentrated in vacuo. The crude material was purified bychromatography on SiO₂ (EtOAc/hexanes, 1:2) to afford3-fluoro-2-(4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazin-1-yl)benzonitrile(260 mg, 3% over 3 steps) as a light yellow solid. Mp: 127-129° C.; IR(neat): 2224, 1629, 1464, 1432, 1321, 1281, 1127, 1067, 1032 cm⁻¹;¹H-NMR (500 MHz; CDCl₃): δ 7.68 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.5 Hz,2H), 7.41 (d, J=7.7 Hz, 1H), 7.29 (dd, J=8.4, 1.4 Hz, 1H), 7.28-7.26(dd, J=8.5, 1.4 Hz, 1H), 4.01 (t, J=4.9 Hz, 2H), 3.89 (t, J=5.0 Hz, 2H),3.39 (t, J=4.0 Hz, 2H), 3.32 (t, J=4.0 Hz, 2H). ¹³C-NMR (125 MHz;CDCl₃): δ 158.4 (d, J=250.3 Hz), 152.7, 141.7 (d, J=12.7 Hz), 132.6,131.8 (d, J=32.8 Hz), 129.6 (d, J=3.4 Hz), 125.5 (q, J=3.8 Hz), 125.4(d, J=8.4 Hz), 124.2 (d, J=1.4 Hz), 123.6 (q, J=108.4 Hz), 121.8, 121.6,117.0 (d, J=4.5 Hz), 111.7 (d, J=6.3 Hz), 51.9 (d, J=4.4 Hz), 51.2 (d,J=4.6 Hz), 47.9, 42.4; ¹⁹F-NMR (470 MHz; CDCl₃): δ −63.08 (s, 3 F),−119.85 (d, J=11.3 Hz, 1 F); HRMS (ESI): m/z calculated for C₂₁H₁₆F₄N₃O([M+H]⁺) 402.1224, found 402.1223.

3-Fluoro-2-(4-(2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile.To a solution of3-fluoro-2-(4-(3-(4-(trifluoromethyl)phenyl)propioloyl)piperazin-1-yl)benzonitrile(0.240 g, 0.598 mmol) in EtOAc (5.98 mL, 0.1 M) was added Pd/BaSO₄ (5%Pd on CaCO₃, lead poisoned, 0.0636 g, 5.0 mol %). The reaction vesselwas placed under vacuum and backfilled with H2 (balloon, 2×) and allowedto stir for 21 h. Then the reaction mixture was then filtered throughcelite, washed with EtOAc and concentrated in vacuo. The crude residuewas purified by chromatography on SiO₂ (hexanes/EtOAc, 1:1) to afford3-fluoro-2-(4-(2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)piperazin-1-yl)benzonitrile(0.213 g) as a light yellow oil. This product was used without furtherpurification.

To a solution of anhydrous CrCl₂ (0.364 g, 2.87 mmol) in THF (4.78 mL)that was degassed by sparging with Ar for 30 min followed by theaddition of the above product (0.193 g, 0.478 mmol) and CH₂ICl (0.178mL, 2.39 mmol) at RT and under Ar atmosphere. The reaction mixture wasstirred at 80° C. After stirring for 14.5 h, the reactions were wascooled to RT and added to EtOAc (30 mL). Then the mixture wassequentially washed with 1.0 M aqueous HCl (30 mL×3) and saturatedaqueous sodium thiosulfate (30 mL×2). The resulting organic phase wasdried (Na₂SO₄), filtered and concentrated in vacuo. The crude materialwas diluted with EtOAc (5 mL) and filtered through basic aluminum. Thisprocess was repeated two times to remove residual chromium. Then themixture was purified by chromatography on SiO₂ (EtOAc/hexanes, 1:1) toafford3-fluoro-2-(4-(2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carbonyl)-piperazin-1-Abenzonitrileas a brown viscous oil (21.4 mg, 10% over 2 steps): IR (neat): 2233,1639, 1465, 1436, 1325, 1163, 1116, 1069, 1028 cm⁻¹; ¹H-NMR (400 MHz;CDCl₃): δ 7.53 (d, J=8.1 Hz, 2H), 7.34 (ddd, J=7.7, 1.4, 0.8 Hz, 1H),7.28 (d, J=8.3 Hz, 2H), 7.20 (ddd, J=12.0, 8.3, 1.4 Hz, 1H), 7.07 (td,J=8.1, 4.7 Hz, 1H), 3.97-3.92 (m, 1H), 3.80-3.75 (m, 1H), 3.66-3.60 (m,1H), 3.33-3.27 (m, 1H), 3.11-3.04 (m, 2H), 2.72-2.67 (m, 1H), 2.54-2.45(m, 2H), 2.27 (ddd, J=9.2, 8.4, 6.2 Hz, 1H), 1.92 (q, J=6.2 Hz, 1H),1.43 (td, J=8.4, 5.6 Hz, 1H); ¹³C-NMR (125 MHz; CDCl₃): δ 166.7, 158.5(d, J=251.5 Hz), 141.8 (d, J=1.8 Hz), 141.7 (d, J=9.4 Hz), 129.4 (d,J=3.2 Hz), 128.7 (q, J=32.3 Hz), 127.8, 125.2 (q, J=7.1 Hz), 125.1 (q,J=3.7 Hz), 124.2 (q, J=270.1 Hz), 121.7, 121.5, 116.9 (d, J=4.5 Hz),111.8 (d, J=6.4 Hz), 51.9 (d, J=4.2 Hz), 51.3 (d, J=5.0 Hz), 46.0, 42.6,24.5, 24.0, 11.1; ¹⁹F-NMR (376 MHz; CDCl₃): δ −62.47 (s, 3 F), −119.74(d, J=11.3 Hz, 1 F). HRMS (ESI): m/z calculated for C₂₂H₂₀ON₃F₄ ([M+H]⁺)418.1537, found 418.1537.

1-(2-Chloro-5-(trifluoromethyl)phenyl)piperazine hydrochloride. Under N₂atmosphere, CuBr (0.565 g, 3.86 mmol), 1,1′-bi-2-naphthol (0.830 g, 2.89mmol) and DMF (9.65 mL) was added to the flame-dried flask. The mixturewas stirred for 10 minutes before the addition of 1-Boc-piperazine (5.39g, 28.9 mmol), K₃PO₄ (8.44 g, 38.6 mmol) and2-bromo-1-chloro-4-(trifluoromethyl)benzene (3.00 mL, 19.3 mmol). Thereaction mixture was stirred at RT for 24 h. Then the mixture wasstirred at 100° C. for 22 h. After cooling to room temperature, themixture was diluted with EtOAc (20 mL) and filtered through Celite pad.The filtrate was concentrated under reduced pressure. Then the residuewas sequentially washed with sat. NH₄Cl aq. (150 mL×2) and brine (150mL×2). The resulting organic layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude product was filteredthrough a short column of SiO₂ (EtOAc/hexanes, 1:9) to remove unreactedpiperazines. And the obtained mixture (2.96 g) was used without furtherpurification.

To a solution of the above product (2.96 g) in 1,4-dioxane (19.9 mL),HCl (4 M in 1,4-dioxane, 8.11 mL) was added at 0° C. The mixture wasstirred at RT for 14 h. The thick suspension was diluted with hexanes(50 mL) and the resulting solid was collected by filtration, washed withhexanes and Et₂O, and dried to give1-(2-chloro-5-(trifluoromethyl)phenyl)piperazine hydrochloride as alight yellow solid (0.408 g, 11% yield over 2 steps). Mp: 270° C.(decomposition); IR (neat): 2937, 2816, 2725, 2495, 1423, 1305, 1178,1156, 1114, 1084, 1044 cm⁻¹; ¹H-NMR (400 MHz; DMSO-d6): δ 9.49 (s, 1H),9.41 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.45 (s,1H), 3.24 (brs, 4H); ¹³C-NMR (125 MHz; DMSO-d6): δ 148.6, 131.8, 131.5,128.8 (q, J=32.2 Hz), 123.7 (q, J=272.5 Hz), 121.1 (q, J=3.9 Hz), 117.6(q, J=3.6 Hz), 47.4, 42.9; ¹⁹F-NMR (376 MHz; DMSO-d6): δ −60.94 (d,J=2.8 Hz, 1 F); HRMS (ESI): m/z calculated for C₁₁H₁₃F₃N₂Cl ([M+H]⁺)265.0714, found 265.0710.

1-(4-(2-Chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one.To a solution of 3-(4-(trifluoromethyl)phenyl)propiolic acid (0.300 g,1.40 mmol) in CH₂Cl₂ (14.0 mL) at 0° C. was added1-(2-chloro-5-(trifluoromethyl)phenyl)piperazine hydrochloride (0.506 g,1.68 mmol), and Et₃N (0.597 mL, 4.20 mmol). T₃P (1.49 mL, 2.10 mmol) wasadded dropwise and the reaction was stirred at 0° C. for 30 min andallowed to warm to RT for 23.5 h. Then the reaction was diluted withCH₂Cl₂ (30 mL) and washed with 1 M HCl (30 mL). The aqueous phase wasextracted with CH₂Cl₂ (30 mL×3) and combined organic phase was dried(Na₂SO₄), filtered and concentrated in vacuo. The crude material waspurified by chromatography on SiO₂ (EtOAc/hexanes, 1:3) to afford1-(4-(2-chloro-5-(trifluoromethyl)-phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(641 mg, 99%) as a yellow solid: Mp: 124-125° C.; IR (neat): 2225, 1631,1419, 1321, 1310, 1276, 1167, 1122, 1107, 1086, 1068, 1035, 1017 cm⁻¹;¹H-NMR (500 MHz; CDCl₃): δ 7.68 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz,2H), 7.51 (d, J=8.3 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.24 (d, J=1.5 Hz,1H), 4.03 (t, J=4.9 Hz, 2H), 3.91 (t, J=4.9 Hz, 2H), 3.18 (t, J=4.9 Hz,2H), 3.11 (t, J=4.9 Hz, 2H); ¹³C-NMR (125 MHz; CDCl₃): δ 152.6, 149.0,132.7, 132.6, 131.8 (q, J=32.9 Hz), 131.3, 130.2 (q, J=32.9 Hz), 125.5(q, J=3.7 Hz), 124.1, 123.6 (q, J=271.0 Hz), 121.0 (q, J=3.8 Hz), 117.5(q, J=3.6 Hz), 89.1, 82. 7, 51.4, 50.7, 47.2, 41.7; ¹⁹F-NMR (471 MHz;CDCl₃): δ−62.58 (s, 1 F), −63.10 (s, 1 F); HRMS (ESI): m/z calculatedfor C₂₀H₁₄ON₃ClF₆ ([M+H]⁺) 461.0724, found 461.0639.

(4-(2-Chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanone.Under Ar atmosphere, a solution of1-(4-(2-chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.610 g, 1.32 mmol) in EtOAc (13.2 mL) was treated with quinoline(0.806 mL, 6.62 mmol) and 5% Pd/BaSO₄ (0.0282 g, 5 mol % based on Pd).The reaction was placed under a balloon of H₂ (3 vacuum/backfill cycles)and stirred at RT for 4 h. The reaction was filtered through Celite(eluting with EtOAc (100 mL) and the filtrates were washed with 1Maqueous HCl (100 mL). The organic phase was concentrated in vacuo toafford a crude product as a brown solid. The crude product was purifiedby chromatography on SiO₂ (EtOAc/hexanes, 1:2) to give the correspondingalkene (0.530 g, 86%) as a white crystal. ¹H-NMR (400 MHz; CDCl₃): δ7.61 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.46 (dd, J=8.4, 0.7 Hz,1H), 7.24 (dd, J=8.4, 0.7 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.76 (d,J=12.6 Hz, 1H), 6.21 (d, J=12.6 Hz, 1H), 3.86 (t, J=4.8 Hz, 2H), 3.54(t, J=5.0 Hz, 2H), 3.00 (t, J=5.0 Hz, 2H), 2.66 (t, J=4.9 Hz, 2H).¹⁹F-NMR (376 MHz; CDCl₃): δ −62.69 (s, 1 F), −62.79 (s, 1 F).

To a solution of anhydrous CrCl₂ (0.134 g, 1.06 mmol) in THF (1.80 mL)that was degassed by sparging with Ar for 10 min followed by theaddition of(Z)-1-(4-(2-chloro-5-(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(0.469 g, 1.01 mmol) and CH₂ICl (0.376 mL, 5.06 mmol) at RT and under Aratmosphere. The reaction mixture was stirred at 80° C. After stirringfor 21 h, the reaction was cooled to RT and then diluted with EtOAc (50mL). The organic layer was sequentially washed with 1 M aqueous HCl (50mL×3) and sat. aqueous sodium thiosulfate (50 mL×2). Then the organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was diluted in minimum amount of EtOAc and the solution wasfiltered through a plug of basic alumina two times. The resulting crudematerial was purified by chromatography on SiO₂ (EtOAc/hexanes, 1:2) toafford(4-(2-chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.332 g, 69%) as a white solid: Mp: 122-123° C.; IR (neat): 1641, 1619,1437, 1418, 1326, 1308, 1166, 1117, 1085, 1070, 1031 cm⁻¹; ¹H-NMR (500MHz; CDCl₃): δ 7.55 (d, J=8.2 Hz, 2H), 7.46 (dd, J=8.3, 0.6 Hz, 1H),7.31 (d, J=8.2 Hz, 2H), 7.25 (dd, J=8.3, 1.7 Hz, 1H), 6.98 (d, J=1.7 Hz,1H), 3.94 (d, J=13.0 Hz, 1H), 3.77 (d, J=13.0 Hz, 1H), 3.67 (td, J=10.7,2.8 Hz, 1H), 3.37 (ddd, J=12.5, 9.2, 2.8 Hz, 1H), 3.00 (t, J=12.5 Hz,2H), 2.54 (q, J=8.0 Hz, 1H), 2.38 (t, J=8.8 Hz, 1H), 2.30 (ddd, J=9.3,8.4, 6.2 Hz, 1H), 2.16 (t, J=8.8 Hz, 1H), 1.94 (q, J=6.2 Hz, 1H), 1.46(td, J=8.4, 5.6 Hz, 1H); ¹³C-NMR (125 MHz; CDCl₃): δ 166.7, 149.0,141.9, 132.5 (d, J=1.2 Hz), 131.1, 130.2 (q, J=32.7 Hz), 128.8 (q,J=32.5 Hz), 127.8, 125.0 (q, J=3.7 Hz), 124.1 (q, J=270.5 Hz), 123.5 (q,J=270.8 Hz), 120.8 (q, J=3.8 Hz), 117.2 (q, J=3.7 Hz), 51.4, 50.8, 45.2,41.9, 24.6, 24.0, 11.2; ¹⁹F-NMR (471 MHz; CDCl₃): δ −62.53 (s, 1 F),−62.76 (s, 1 F); HRMS (ESI): m/z calculated for C₂₂H₂₀F₆N₂ClO ([M+H]⁺)477.1163, found 477.1152.

Racemic(4-(2-chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (15%MeOH, 7 mL/min, 220 nM, P=100) to afford(4-(2-chloro-5-(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(retention time; 5.70 min) as a white solid (>99.9% purity by ELSD):[α]¹⁸ _(D)−127.0 (c=0.29, MeOH); HRMS (ESI): m/z calculated forC₂₂H₂₀F₆ON₂Cl ([M+H]⁺) 477.1163, found 477.1164. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 15% MeOH, 220 nM, 7 mL/min;retention time: 5.70 min). ¹H-NMR (500 MHz; CDCl₃): δ 7.55 (d, J=8.2 Hz,2H), 7.46 (dd, J=8.3, 0.6 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.25 (dd,J=8.3, 1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 3.94 (d, J=13.0 Hz, 1H),3.77 (d, J=13.0 Hz, 1H), 3.67 (td, J=10.7, 2.8 Hz, 1H), 3.37 (ddd,J=12.5, 9.2, 2.8 Hz, 1H), 3.00 (t, J=12.5 Hz, 2H), 2.54 (q, J=8.0 Hz,1H), 2.38 (t, J=8.8 Hz, 1H), 2.30 (ddd, J=9.3, 8.4, 6.2 Hz, 1H), 2.16(t, J=8.8 Hz, 1H), 1.94 (q, J=6.2 Hz, 1H), 1.46 (td, J=8.4, 5.6 Hz, 1H).

(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone;(retention time; 6.40 min) as a white solid (>99.9% purity by ELSD):[α]¹⁸ _(D)+130.0 (c=0.23, MeOH); HRMS (ESI): m/z calculated forC₂₂H₂₀F₆ON₂Cl ([M+H]⁺) 477.1163, found 477.1160. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 15% MeOH, 220 nM, 7 mL/min;retention time: 6.40 min). ¹H-NMR (500 MHz; CDCl₃): δ 7.55 (d, J=8.2 Hz,2H), 7.46 (dd, J=8.3, 0.6 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.25 (dd,J=8.3, 1.7 Hz, 1H), 6.98 (d, J=1.7 Hz, 1H), 3.94 (d, J=13.0 Hz, 1H),3.77 (d, J=13.0 Hz, 1H), 3.67 (td, J=10.7, 2.8 Hz, 1H), 3.37 (ddd,J=12.5, 9.2, 2.8 Hz, 1H), 3.00 (t, J=12.5 Hz, 2H), 2.54 (q, J=8.0 Hz,1H), 2.38 (t, J=8.8 Hz, 1H), 2.30 (ddd, J=9.3, 8.4, 6.2 Hz, 1H), 2.16(t, J=8.8 Hz, 1H), 1.94 (q, J=6.2 Hz, 1H), 1.46 (td, J=8.4, 5.6 Hz, 1H).

1-(2,5-Bis(trifluoromethyl)phenyl)piperazine hydrochloride. Under N₂atmosphere, CuBr (0.511 g, 3.49 mmol), 1,1′-bi-2-naphthol (0.751 g, 2.62mmol) and DMF (8.73 mL) was added to the flame-dried flask. The mixturewas stirred for 10 minutes before the addition of 1-Boc-piperazine (4.88g, 26.2 mol), K₃PO₄ (7.64 g, 34.9 mmol) and the2,5-bis(trifluoromethyl)bromobenzene (3.00 mL, 17.5 mmol). The mixturewas stirred at 100° C. for 26.5 h. After cooling to room temperature,the mixture was diluted with EtOAc (20 mL) and filtered through celitepad. The filtrate was concentrated under reduced pressure. Then theresidue was sequentially washed with sat. NH₄Cl aq. (150 mL×2) and brine(150 mL×2). The resulting organic layer was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude product was filteredthrough a short column of SiO₂ (EtOAc/hexanes 1:9) to remove unreactedpiperazines. And the obtained mixture (2.76 g) was used without furtherpurification.

To a solution of the above product (2.76 g) in 1,4-dioxane (17.0 mL),HCl (4 M in 1,4-dioxane, 6.93 mL) was added at 0° C. The mixture wasstirred at RT for 16 h. The thick suspension was diluted with hexanes(50 mL) and the resulting solid was collected by filtration, washed withhexanes and dried to give 1-(2,5-bis(trifluoromethyl)phenyl)piperazinehydrochloride as a white fluffy solid (0.811 g, 16% over 2 steps): Mp:268° C.; IR (neat): 2722, 2478, 1569, 1424, 1311, 1180, 1117, 1081, 1038cm⁻¹; ¹H-NMR (500 MHz; DMSO-d6): δ 9.47-9.29 (brs, 2H), 7.82 (s, 1H),7.78 (d, J=8.2 Hz, 1H), 3.18 (s, 4H); ¹³C-NMR (125 MHz; DMSO-d6): δ152.1, 134.3 (q, J=32.5 Hz), 129.6 (q, J=28.7 Hz), 129.3 (q, J=5.1 Hz),123.6 (q, J=274.0 Hz), 123.1 (d, J=3.6 Hz), 121.8 (d, J=3.4 Hz), 50.0,43.6; ¹⁹F-NMR (471 MHz; DMSO-d6): δ −59.66 (s, 3 F), −61.67 (s, 3 F);HRMS (ESI): m/z calculated for C₁₂H₁₃F₆N₂ ([M+H]⁺) 299.0977, found299.0971.

1-(4-(2,5-Bis(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one.To a solution of 3-(4-(trifluoromethyl)phenyl)propiolic acid (0.300 g,1.40 mmol) in CH₂Cl₂ (14.0 mL) at 0° C. was added1-(2,5-bis(trifluoromethyl)phenyl)piperazine hydrochloride (0.563 g,1.68 mmol), and Et₃N (0.597 mL, 4.20 mmol). T₃P (1.49 mL, 2.10 mmol) wasadded dropwise and the reaction was stirred at 0° C. for 30 min andallowed to warm to RT for 23.5 h. The reaction was diluted with CH₂Cl₂(30 mL) and washed with 1 M HCl (30 mL). The aqueous phase was extractedwith CH₂Cl₂ (30 mL×3) and combined organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo. The crude material was purified bychromatography on SiO₂ (EtOAc/hexanes, 1:3) to afford1-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(155 mg, 50%) as a light yellow oil: IR (neat): 1632, 1424, 1311, 1285,1274, 1172, 1121, 1107, 1034 cm⁻¹; ¹H-NMR (500 MHz; CDCl₃): δ 7.80 (d,J=8.1 Hz, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.56 (s,1H), 7.55 (d, J=8.1 Hz, 1H), 3.99 (t, J=4.9 Hz, 2H), 3.87 (t, J=4.9 Hz,2H), 3.06 (t, J=4.9 Hz, 2H), 2.99 (t, J=4.9 Hz, 2H); ¹³C-NMR (125 MHz;CDCl₃): δ 152.6, 152.1, 135.2 (q, J=33.3 Hz), 132.6, 131.8 (q, J=32.9Hz), 130.7 (q, J=29.6 Hz), 128.4 (q, J=5.4 Hz), 125.5 (q, J=3.7 Hz),124.1 (d, J=1.8 Hz), 123.6 (q, J=270.8 Hz), 123.2 (q, J=272.0 Hz), 123.1(q, J=271.0 Hz), 122.4 (q, J=3.6 Hz), 121.1 (q, J=3.5 Hz), 89.1, 82.7,53.6, 52.8, 47.4, 41.9. ¹⁹F-NMR (471 MHz; CDCl₃): δ −60.91 (s, 3 F),−63.12 (s, 3 F), −63.23 (s, 3 F); HRMS (ESI): m/z calculated forC₂₂H₁₆F₉ON₂ ([M+H]⁺) 495.1113, found 495.0934

(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanone.Under Ar atmosphere, a solution of1-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.657 g, 1.33 mmol) in EtOAc (13.3 mL) was treated with quinoline(0.810 mL, 6.65 mmol) and 5% Pd/BaSO₄ (0.0283 g, 10 mol % based on Pd).The reaction was placed under a balloon of H₂ (3 vacuum/backfill cycles)and stirred at RT for 6 h. The reaction was filtered through Celite(eluting with EtOAc (100 mL) and the filtrates were washed with 1Maqueous HCl (100 mL×2). The organic phase was dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified bychromatography on SiO₂ (EtOAc/hexanes, 2:3) to give(Z)-1-(4-(2,5-bis(trifluoromethyl)phenyl)-piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(0.655 g, 99%) as a light yellow oil. ¹H-NMR (400 MHz; CDCl₃): δ 7.75(d, J=8.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.50(d, J=8.2 Hz, 1H), 7.33 (s, 1H), 6.75 (d, J=12.5 Hz, 1H), 6.21 (d,J=12.5 Hz, 1H), 3.82 (t, J=4.9 Hz, 2H), 3.51 (t, J=4.9 Hz, 2H), 2.87 (t,J=4.9 Hz, 2H), 2.51 (t, J=4.9 Hz, 2H). ¹⁹F-NMR (376 MHz; CDCl₃): δ−60.96 (s, 3 F), −62.82 (s, 3 F), −63.35 (s, 3 F).

To a solution of anhydrous CrCl₂ (0.850 g, 6.71 mmol) in THF (11.2 mL)that was degassed by sparging with Ar for 10 min followed by theaddition of(Z)-1-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one(0.555 g, 1.12 mmol) and CH₂ICl (0.416 mL, 5.59 mmol) at RT and under Aratmosphere. The reaction mixture was stirred at 80° C. After stirringfor 22.5 h, the reaction was cooled to RT and then diluted with EtOAc(80 mL). The solution was sequentially washed with 1 M aqueous HCl (80mL×3) and sat. aqueous sodium thiosulfate (100 mL×2). Then the organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was diluted with minimum amount of EtOAc, and the solution wasfiltered through a plug of basic alumina. This process was repeated twotimes. Then the resulting crude material was purified by chromatographyon SiO₂ (EtOAc/hexanes, 2:1) to afford(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)-phenyl)cyclopropyl)methanone(0.472 g, 83%) as a white solid: Mp: 111-112° C.; IR (neat): 1644, 1425,1327, 1314, 1123, 1032 cm⁻¹; ¹H-NMR (500 MHz; CDCl₃): δ 7.72 (d, J=8.2Hz, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2Hz, 2H), 7.18 (s, 1H), 3.96 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.6 Hz, 1H),3.56 (t, J=9.9 Hz, 1H), 3.23 (t, J=9.9 Hz, 1H), 2.78 (t, J=15.3 Hz, 2H),2.51 (q, J=7.9 Hz, 1H), 2.29-2.23 (m, 2H), 2.05 (t, J=9.0 Hz, 1H), 1.92(q, J=6.2 Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H); ¹³C-NMR (125 MHz;CDCl₃): δ 166.6, 152.2, 142.0, 135.1 (q, J=33.0 Hz), 128.8 (q, J=32.6Hz), 128.1 (q, J=5.4 Hz), 127.9, 124.9 (q, J=3.7 Hz), 124.1 (q, J=269.9Hz), 123.1 (q, J=270.9 Hz), 123.0 (q, J=271.1 Hz), 122.0 (q, J=3.6 Hz),120.7 (q, J=3.4 Hz), 53.7, 52.9, 45.4, 42.1, 24.6, 23.9, 11.1. ¹⁹F-NMR(471 MHz; CDCl₃): δ −60.98 (s, 3 F), −62.58 (s, 3 F), −63.48 (s, 3 F);HRMS (ESI): m/z calculated for C₂₃H₂₀F₉ON₂ ([M+H]⁺) 511.1426, found511.1426.

Racemic(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)-methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (5%MeOH, 7 mL/min, 220 nM, P=100) to afford(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)((1S,2R)-2-(4-(trifluoromethyl)-phenyl)cyclopropyl)methanone(retention time; 7.60 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)−109.7 (c=0.25, MeOH); HRMS (ESI): m/z calculated forC₂₃H₂₀F₉ON₂ ([M+H]⁺) 511.1426, found 511.1423. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 5% MeOH, 220 nM, 7 mL/min;retention time: 7.60 min). (500 MHz; CDCl₃): δ 7.72 (d, J=8.2 Hz, 1H),7.54 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H),7.18 (s, 1H), 3.96 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.6 Hz, 1H), 3.56 (t,J=9.9 Hz, 1H), 3.23 (t, J=9.9 Hz, 1H), 2.78 (t, J=15.3 Hz, 2H), 2.51 (q,J=7.9 Hz, 1H), 2.29-2.23 (m, 2H), 2.05 (t, J=9.0 Hz, 1H), 1.92 (q, J=6.2Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H).

(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)((1R,2S)-2-(4-(trifluoromethyl)phenyl)-cyclopropyl)methanone;(retention time; 9.20 min) as a colorless oil (>99.9% purity by ELSD):[α]¹⁸ _(D)+108.8 (c=0.22, MeOH); HRMS (ESI): m/z calculated forC₂₃H₂₃F₆O₂N₂ ([M+H]⁺) 511.1426, found 511.1425. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 5% MeOH, 220 nM, 7 mL/min;retention time: 9.20 min). ¹H-NMR (500 MHz; CDCl₃): δ 7.72 (d, J=8.2 Hz,1H), 7.54 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2 Hz,2H), 7.18 (s, 1H), 3.96 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.6 Hz, 1H),3.56 (t, J=9.9 Hz, 1H), 3.23 (t, J=9.9 Hz, 1H), 2.78 (t, J=15.3 Hz, 2H),2.51 (q, J=7.9 Hz, 1H), 2.29-2.23 (m, 2H), 2.05 (t, J=9.0 Hz, 1H), 1.92(q, J=6.2 Hz, 1H), 1.43 (td, J=8.4, 5.6 Hz, 1H).

(4-Cyclohexylpiperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone.To a solution ofpiperazin-1-yl(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanonehydrochloride (0.09 g, 0.269 mmol) and cyclohexanone (0.0279 mL, 0.269mmol) in dichloromethane (1.00 mL) was added NaBH(OAc)₃ (0.256 g, 1.21mmol) and acetic acid (0.0154 mL, 0.269 mmol). The mixture was stirredfor 45 h at room temperature. Then the mixture was quenched with 1Naqueous NaOH (40 mL) and extracted with EtOAc (40 mL×3). The combinedorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified by chromatography on SiO₂ (MeOH/CH₂Cl₂,1:9) to yield(4-cyclohexylpiperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0883 g, 86%) as a light yellow solid: Mp: 99-101° C.; IR (neat):2933, 1634, 1618, 1468, 1439, 1325, 1161, 1116, 1070, 1017 cm⁻¹; ¹H-NMR(500 MHz; CDCl₃): δ 7.49 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 3.78(d, J=12.8 Hz, 1H), 3.58 (d, J=12.8 Hz, 1H), 3.38 (ddd, J=12.5, 9.4, 3.0Hz, 1H), 3.06 (ddd, J=12.5, 9.4, 3.0 Hz, 1H), 2.47-2.41 (m, 3H), 2.22(td, J=8.8, 6.3 Hz, 1H), 2.09 (tt, J=11.4, 3.1 Hz, 1H), 1.87-1.82 (m,2H), 1.73 (d, J=12.8 Hz, 2H), 1.61-1.57 (m, 4H), 1.39 (td, J=8.4, 5.6Hz, 1H), 1.19-1.10 (m, 2H), 1.06-0.94 (m, 3H); ¹³C-NMR (125 MHz; CDCl₃):δ 166.3, 142.2, 128.5 (q, J=32.4 Hz), 127.8, 124.9 (q, J=3.9 Hz), 124.2(q, J=270.0 Hz), 63.5, 49.2, 48.4, 45.6, 42.3, 28.6, 28.5, 26.2, 25.8,24.8, 23.8, 11.2; ¹⁹F-NMR (471 MHz; CDCl₃): δ −62.43 (s, 3 F); HRMS(ESI): m/z calculated for C₂₃H₂₀F₉ON₂ ([M+H]⁺) 381.2154, found 381.2147.

(4-(Tetrahydro-2H-pyran-4-yl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone.To a solution ofpiperazin-1-yl(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanonehydrochloride (0.09 g, 0.269 mmol) and tetrahydro-4H-pyran-4-one (0.0269mL, 0.269 mmol) in dichloromethane (1.00 mL) was added NaBH(OAc)₃ (0.205g, 0.269 mmol) and acetic acid (0.0154 mL, 0.269 mmol). The mixture wasstirred for 13 h at room temperature. Then the mixture was quenched with1N aqueous NaOH (30 mL) and extracted with CH₂Cl₂ (30 mL×3). Thecombined organic phase was dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified by chromatography on SiO₂(MeOH:CH₂Cl₂=1:9) to give(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)(2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone(0.0845 g, 82%) as a light yellow solid: Mp: 84-86° C.; IR (neat): 2949,2845, 1637, 1619, 1468, 1439, 1325, 1161, 1115, 1069 cm⁻¹; ¹H-NMR (500MHz; CDCl₃): δ 7.49 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 3.95 (dd,J=11.5, 3.4 Hz, 2H), 3.83 (d, J=13.1 Hz, 1H), 3.61 (d, J=12.9 Hz, 1H),3.37 (ddd, J=12.7, 9.5, 3.1 Hz, 1H), 3.28 (tt, J=11.8, 2.8 Hz, 2H), 3.04(ddd, J=12.7, 9.5, 3.1 Hz, 1H), 2.47-2.43 (m, 3H), 2.28-2.19 (m, 2H),1.87-1.78 (m, 2H), 1.51-1.30 (m, 6H). ¹³C-NMR (125 MHz; CDCl₃): δ 166.3,142.2, 128.5 (q, J=32.4 Hz), 127.7, 125.0 (q, J=3.9 Hz), 124.2 (q,J=270.4 Hz), 67.4, 67.3, 60.8, 49.0, 48.6, 45.4, 42.1, 29.1, 28.9, 24.9,23.8, 11.3; ¹⁹F-NMR (471 MHz; CDCl₃): δ −62.37 (s, 3 F); HRMS (ESI): m/zcalculated for C₂₀H₂₆F₃O₂N₂ ([M+H]⁺) 383.1946, found 383.1938.

2-Hydroxy-4-oxo-4-(4-(trifluoromethyl)phenyl)but-2-enoic acid. To aheterogeneous solution of Na (0.121 g, 5.26 mmol) in Et₂O (2.56 mL) wasadded dropwise dry EtOH (0.307 mL) at 0° C. The mixture was stirred for20 min at that temperature. Then a mixture of dimethyl oxalate (0.583mL, 5.26 mmol) and 4′-(trifluoromethyl)acetophenone (1.00 g, 5.26 mmol)in dry Et₂O (0.850 mL) was added carefully in small portions at −20° C.and stirred for 19.5 h at that temperature. The mixture was then pouredinto 1N HCl and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated undervacuum. The resulting crude product was used without furtherpurification.

To a 250-mL round-bottom flask was added the above product (1.51 g) inTHF (6.55 mL), followed by LiOH monohydrate (1.10 g, 26.2 mmol) in water(6.55 mL) in one portion. Saponification was terminated when thestarting material was consumed completely by TLC analysis (petroleumether/EtOAc, 1:1). The mixture was concentrated under vacuum to removethe THF and then was extracted with CH₂Cl₂ (100 mL×3). The aqueous layerwas acidified with 1N HCl (100 mL) and extracted with EtOAc (100 mL×3).The combined organic layer was dried (Na₂SO₄), filtered and concentratedin vacuo to yield2-hydroxy-4-oxo-4-(4-(trifluoromethyl)phenyl)but-2-enoic acid (0.311 g,23% over 2 steps) as a white solid. ¹H-NMR (300 MHz; CDCl₃): δ 8.12 (d,J=8.2 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 7.20 (s, 1H). The spectraobtained are in agreement with previously reported data (Zeng et al.,Bioorg. Med. Chem. 2008, 16:7777-7787).

3-Hydroxy-5-(4-(trifluoromethyl)phenyl)dihydrofuran-2(3H)-one. To a100-mL round-bottom flask containing a stirrer,2-hydroxy-4-oxo-4-(4-(trifluoromethyl)phenyl)but-2-enoic acid (1.03 g,3.96 mmol) in 13.2 mL MeOH was added, followed by NaBH₄ (0.611 g, 15.8mmol) in small portions at room temperature. The mixture was stirred for3 h. 1 mL water was added to decompose residual NaBH₄ and the mixturewas concentrated under vacuum to remove the solvent. Then the mixturewas acidified to pH 1.0-2.0 by adding 1N HCl (10 mL) and refluxed for17.5 h. Then the mixture was extracted with EtOAc (50 mL×3) and thecombined organic layer was dried (Na₂SO₄), filtered and concentrated invacuo. The crude mixture was purified by chromatography on SiO₂(CH₂Cl₂/MeOH, 20:1) to afford3-Hydroxy-5-(4-(trifluoromethyl)-phenyl)dihydrofuran-2(3H)-one (0.456 g,47%, dr=1:2) as a white solid: IR (neat): 3421, 1772, 1322, 1166, 1110,1067, 1016 cm⁻¹; (Major diastereomer) ¹H-NMR (500 MHz; CDCl₃): δ 7.68(d, J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 5.43 (dd, J=10.9, 5.4 Hz,1H), 4.73 (t, J=9.6 Hz, 1H), 3.06 (ddd, J=12.9, 7.9, 5.2 Hz, 1H), 3.01(d, J=0.4 Hz, 1H), 2.21 (q, J=11.8 Hz, 1H); ¹³C-NMR (125 MHz; CDCl₃): δ176.9, 141.8, 131.1 (q, J=32.7 Hz), 126.0, 125.9 (q, J=4.0 Hz), 123.8(q, J=272.4 Hz), 77.9, 68.8, 39.5; ¹⁹F-NMR (471 MHz; CDCl₃): δ −62.74(s, 3 F).

2-Oxo-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yltrifluoromethanesulfonate. To a solution of3-hydroxy-5-(4-(trifluoromethyl)phenyl)dihydrofuran-2(3H)-one (0.140 g,0.569 mmol) and pyridine (0.0696 mL, 0.853 mmol) in dry CH₂Cl₂ (2.84 mL)was added trifluoromethanesulfonic anhydride (0.116 mL) at 0° C. Themixture was stirred for 1.5 h at that temperature. Then the mixture wasdiluted with CH₂Cl₂ (15 mL) and quenched with 1N aqueous HCl (15 mL).The aqueous layer was extracted with CH₂Cl₂ (15 mL×3) and a combinedorganic layer was dried (Na₂SO₄), filtered and concentrated in vacuo.The crude mixture was purified by chromatography on SiO₂ (hexanes/EtOAc,3:1) to yield 2-oxo-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yltrifluoromethanesulfonate (0.586 g, 89%, dr=2:1) as a light yellowsolid. (Major-diastereomer) ¹H-NMR (400 MHz; CDCl₃): δ 7.72 (d, J=8.3Hz, 3H), 7.50 (d, J=8.2 Hz, 2H), 5.61 (dd, J=10.6, 8.4 Hz, 1H), 5.52(dd, J=10.6, 5.5 Hz, 1H), 3.29 (ddd, J=13.0, 8.4, 5.5 Hz, 1H), 2.52 (dt,J=13.0, 10.7 Hz, 1H).

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(4-(4-(trifluoromethyl)phenyl)oxetan-2-yl)methanone.To a solution of 2-oxo-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-yltrifluoromethane-sulfonate (0.0680 g, 0.180 mmol) in dry MeOH (0.899 mL)was added potassium carbonate (0.0301 g, 0.216 mmol). The mixture wasstirred for 1 h at 0° C. Then the mixture was quenched with water,extracted with EtOAc, dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was filtered through a short column of SiO₂(hexanes/EtOAc, 3:1) to yield a mixture of methyl4-(4-(trifluoromethyl)-phenyl)-oxetane-2-carboxylate as a light yellowoil. This product was used without further purification.

To a solution of the above product (97.0 mg) in THF/H₂O (1.85 mL/1.85mL) was added LiOH (62.6 mg, 1.49 mmol) at room temperature. Afterstirring for 16 h, the mixture was diluted with H₂O (10 mL) andextracted with CH₂Cl₂ (15 mL×2). Then the aqueous layer was acidifiedwith 1N HCl (20 mL) and extracted with EtOAc (30 mL×3). The combinedorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was used without further purification.

To a solution of the above crude product (0.095 g) in CH₂Cl₂ (3.86 mL)at 0° C. was added 1-(2-methyl-5-(trifluoromethyl)phenyl)piperazinehydrochloride (0.130 g, 0.463 mmol) and Et₃N (0.164 mL, 1.16 mmol). T₃P(0.409 mL, 0.579 mmol) was added dropwise and the reaction was stirredat 0° C. for 30 min and allowed to warm to RT for 12.5 h. The reactionwas diluted with CH₂Cl₂ (20 mL) and washed with 1 M HCl (20 mL). Theaqueous phase was extracted with CH₂Cl₂ (30 mL×3) and combined organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo. The crudematerial was purified by chromatography on SiO₂ (EtOAc/hexanes, 2:3) toafford(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(4-(4-(trifluoromethyl)phenyl)oxetan-2-yl)methanone(cis-diastereomer (light yellow oil): 96.2 mg, trans-diastereomer (whitesolid): 52.55 mg). (cis-isomer) IR (neat): 2913, 1652, 1445, 1419, 1325,1310, 1163, 1120, 1067 cm⁻¹; ¹H-NMR (500 MHz; CDCl₃): δ 7.64 (d, J=8.2Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0Hz, 1H), 7.19 (s, 1H), 5.73 (t, J=7.7 Hz, 2H), 5.43 (t, J=7.7 Hz, 2H),3.91-3.87 (m, 1H), 3.79-3.72 (m, 2H), 3.61-3.57 (m, 1H), 3.21-3.09 (m,2H), 2.99-2.91 (m, 4H), 2.37 (s, 3H); ¹³C-NMR (125 MHz; CDCl₃): δ168.87, 151.09, 145.93, 136.79, 131.53, 130.35 (q, J=32.4 Hz), 129.05(q, J=32.1 Hz), 126.08, 125.52 (q, J=3.8 Hz), 124.22 (d, J=272.3 Hz),124.0 (d, J=270.5 Hz), 120.37 (q, J=3.8 Hz), 115.99 (q, J=3.6 Hz),78.66, 74.22, 51.89, 51.63, 45.40, 42.39, 32.58, 17.92; ¹⁹F-NMR (471MHz; CDCl₃): δ −62.28 (s, 3F), −62.59 (s, 3F); HRMS (ESI): m/zcalculated for C₂₃H₂₃F₆O₂N₂ ([M+H]⁺) 473.1658, found 473.1649;(trans-isomer) IR (neat): 2918, 1651, 1444, 1418, 1324, 1309, 1163,1119, 1067 cm⁻¹;¹H-NMR (500 MHz; CDCl₃): δ 7.67 (d, J=8.2 Hz, 2H), 7.56(d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.21(s, 1H), 5.80 (t, J=7.4 Hz, 1H), 5.39 (dd, J=8.8, 5.9 Hz, 1H), 3.95-3.92(m, 1H), 3.79-3.76 (m, 1H), 3.72 (ddd, J=13.0, 6.4, 3.0 Hz, 1H),3.59-3.53 (m, 2H), 3.01-2.91 (m, 4H), 2.77 (ddd, J=11.5, 8.8, 6.5 Hz,1H), 2.38 (s, 3H); ¹³C-NMR (125 MHz; CDCl₃): δ 169.2, 151.1, 146.6,136.8 (d, J=1.3 Hz), 131.5, 130.2 (q, J=32.4 Hz), 129.1 (q, J=32.2 Hz),125.6 (q, J=3.8 Hz), 125.4, 124.1 (q, J=272.3 Hz), 124.0 (q, J=270.5Hz), 120.4 (q, J=3.8 Hz), 116.1 (q, J=3.7 Hz), 79.6, 75.4, 51.8, 51.6,45.5, 42.4, 32.3, 18.0; ¹⁹F-NMR (471 MHz; CDCl₃): δ −62.27 (s, 3 F),−62.53 (s, 3 F); HRMS (ESI): m/z calculated for C₂₃H₂₃F₆O₂N₂ ([M+H]⁺)473.1658, found 473.1656.

Racemic(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(4-(4-(trifluoromethyl)phenyl)-oxetan-2-yl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (9%MeOH, 5 mL/min, 220 nM, P=100) to afford (+)-enantiomer (retention time;12.60 min) as a colorless oil (>99.9% purity by ELSD): [α]²⁰ _(D)+55.5(MeOH); HRMS (ESI): m/z calculated for C₂₃H₂₃F₆O₂N₂ ([M+H]⁺) 473.1658,found 473.1656. The enantiomeric excess was >99.9% ee (SFC Chiralpak-ICsemiprep; 9% MeOH, 220 nM, 5 mL/min; retention time: 12.60 min). (500MHz; CDCl₃): δ 7.64 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.30 (d,J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 5.73 (t, J=7.7 Hz,2H), 5.43 (t, J=7.7 Hz, 2H), 3.91-3.87 (m, 1H), 3.79-3.72 (m, 2H),3.61-3.57 (m, 1H), 3.21-3.09 (m, 2H), 2.99-2.91 (m, 4H), 2.37 (s, 3H).

(−)-enantiomer; (retention time; 13.80 min) as a colorless oil (>99.9%purity by ELSD): [α]²⁰ _(D)−70.8 (MeOH); HRMS (ESI): m/z calculated forC₂₃H₂₃F₆O₂N₂ ([M+H]⁺) 473.1658, found 473.1657. The enantiomeric excesswas >99.9% ee (SFC Chiralpak-IC semiprep; 9% MeOH, 220 nM, 5 mL/min;retention time: 13.80 min). (500 MHz; CDCl₃): δ 7.64 (d, J=8.2 Hz, 2H),7.55 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H),7.19 (s, 1H), 5.73 (t, J=7.7 Hz, 2H), 5.43 (t, J=7.7 Hz, 2H), 3.91-3.87(m, 1H), 3.79-3.72 (m, 2H), 3.61-3.57 (m, 1H), 3.21-3.09 (m, 2H),2.99-2.91 (m, 4H), 2.37 (s, 3H).

1-(2-Bromo-1-fluoroethyl)-4-fluorobenzene (Schlossera et al.,Tetrahedron 2004, 7731-7742; Rosen et al., J. Med. Chem. 2004,47:5860-5871). To a stirred solution of 4-fluorostyrene (2.00 g, 1.95mL, 15.9 mmol) in distilled CH₂Cl₂ (16 mL) was added triethylaminetrihydrofluoride (3.96 mL, 23.8 mmol) and NBS (3.43 g, 19.1 mmol) at 0°C. After 15 min, the ice bath was removed and the mixture was stirred atroom temperature for 18 h. The reaction mixture was poured into icewater (200 mL) and made slightly basic with NH₄OH. The mixture wasextracted with CH₂Cl₂ (4×40 mL). The combined organic layers were washedwith 0.1 M HCl (2×40 mL), 5% NaHCO₃ (2×40 mL), dried over anhydrousMgSO₄ and concentrated under reduced pressure. The crude product waspurified via flash column chromatography on SiO₂ (1:20 EtOAc/hexanes) toafford 1-(2-bromo-1-fluoroethyl)-4-fluorobenzene (2.67 g, 12.1 mmol,76%) as a colorless oil: ¹H-NMR (500 MHz, CDCl₃) δ 7.35 (dd, J=8.3, 5.3Hz, 2H), 7.10 (t, J=8.6 Hz, 2H), 5.61 (ddd, J=46.4, 7.5, 4.5 Hz, 1H),3.68 (ddd, J=15.0, 11.3, 7.6 Hz, 1H), 3.59 (ddd, J=24.2, 11.3, 4.4 Hz,1H).

1-Fluoro-4-(1-fluorovinyl)benzene (Schlossera et al., Tetrahedron 2004,7731-7742). To a flame-dried 25-mL round-bottom flask containing1-(2-Bromo-1-fluoroethyl)-4-fluorobenzene (2.66 g, 12.0 mmol) was addedpotassium tert-butoxide (1.49 g, 13.2 mmol) dissolved in distilled THF(6 mL). The mixture was stirred at room temperature for 2 h andfiltered. The red-color filtrate was purified via distillation to give1-fluoro-4-(1-fluorovinyl)benzene (1.16 g, 8.27 mmol, 69%) as acolorless oil (bp 144-146° C.): ¹H NMR (500 MHz, CDCl₃) δ 7.54 (dd,J=8.7, 5.3 Hz, 2H), 7.07 (t, J=8.4 Hz, 2H), 4.96 (dd, J=49.6, 3.6 Hz,2H), 4.83 (dd, J=17.9, 3.6 Hz, 2H).

cis- and trans-Ethyl2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylate (Rosen et al., J.Med. Chem. 2004, 47:5860-5871). In a flame-dried 3-neck round-bottomflask equipped with a stir bar, reflux condenser, septum, and stopper,Cu(acac)₂ (64.9 mg, 0.248 mmol, 3 mol %) was dissolved in distilledCH₂Cl₂ (11 mL). The solution was stirred for several minutes. A fewdrops of phenylhydrazine were added and the stirring continued.1-fluoro-4-(1-fluorovinyl)benzene (1.16 g, 8.27 mmol) was added and themixture was heated to reflux. A solution of ethyl diazoacetate (1.48 mL,12.4 mmol) dissolved in distilled CH₂Cl₂ (22 mL) was added via syringepump over 8 h. The solution was then refluxed for an additional 4 hr,after which it was cooled and diluted with CH₂Cl₂ (150 mL). The solutionwas washed with saturated NaHCO₃ solution and distilled water (300 mL).The organic layer was dried over anhydrous MgSO₄, filtered, andconcentrated under reduced pressure. NMR analysis of the crude productrevealed a conversion of 65%. Purification of the crude product withflash column chromatography on SiO₂ (1:1 CH₂Cl₂/hexanes) afforded amixture of 1:1 cis/trans diastereomers as a yellow oil. Thediastereomers were then separated by flash column chromatography on SiO₂(1:2 CH₂Cl₂/hexanes) to give cis- and trans-ethyl2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylate respectively ascolorless oil: cis-(474 mg, 2.10 mmol, 25%); ¹H NMR (500 MHz, CDCl₃) δ7.32 (dd, J=8.1, 5.2 Hz, 2H), 7.08 (t, J=8.4 Hz, 2H), 4.29-4.19 (m, 2H),2.28 (dt, J=20.1, 7.4 Hz, 1H), 2.15 (ddd, J=9.5, 7.7, 2.7 Hz, 1H), 1.59(ddd, J=10.5, 9.5, 7.1 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz;CDCl₃) δ 167.9 (d, J_(C-F)=2 Hz), 162.9 (dd, J_(C-F)=248, 2 Hz), 133.4(dd, J_(C-F)=22, 3 Hz), 127.3 (dd, J_(C-F)=8, 6 Hz), 115.8 (d,J_(C-F)=22 Hz), 80.7 (d, J_(C-F)=228 Hz), 61.4, 28.8 (d, J_(C-F)=12 Hz),18.8 (d, J_(C-F)=13 Hz), 14.4; ¹⁹F NMR (CDCl₃, 470 MHz) δ −113.2 (s, 1F), −184.9 (s, 1 F).

trans-(481 mg, 2.13 mmol, 26%); ¹H NMR (CDCl₃, 500 MHz) δ 7.48-7.44 (m,2H), 7.06 (t, J=8.4 Hz, 2H), 3.98-3.90 (m, 2H), 2.56 (ddd, J=17.8, 10.3,7.6 Hz, 1H), 1.95 (dt, J=12.2, 7.3 Hz, 1H), 1.82 (ddd, J=19.2, 10.3, 7.1Hz, 1H), 1.04 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 169.0 (d,J_(C-F)=2 Hz), 163.3 (dd, J_(C-F)=249, 3 Hz), 130.6 (dd, J_(C-F)=8, 4Hz), 129.3 (dd, J_(C-F)=21, 3 Hz), 115.5 (dd, J_(C-F)=22, 2 Hz), 82.6(d, J_(C-F)=221 Hz), 60.98, 27.9 (d, J_(C-F)=17 Hz), 16.8 (d, J_(C-F)=11Hz), 14.14; ¹⁹F NMR (CDCl₃, 470 MHz) δ −111.8 (s, 1 F), −152.6 (s, 1 F).

cis-2-Fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid.² To asolution of cis-ethyl2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylate (0.200 g, 0.884mmol) in methanol (1.8 mL) was added KOH (0.500 g, 8.84 mmol) dissolvedin methanol (4.4 ml) at 0° C. The reaction mixture was warm to roomtemperature and stirred for 16 h. The mixture was poured into water andextracted with CH₂Cl₂ (25 mL). The organic layer was discarded and theaqueous layer was acidified with 6 M HCl and extracted with CH₂Cl₂ (2×25mL). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to affordcis-2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (0.171 g,0.864 mmol, 98%) as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ 7.36-7.32(m, 2H), 7.12-7.07 (m, 2H), 2.32 (dt, J=20.1, 7.5 Hz, 1H), 2.18 (ddd,J=9.5, 7.5, 2.2 Hz, 1H), 1.70 (ddd, J=10.7, 9.4, 7.2 Hz, 1H); ¹³C NMR(CDCl₃, 125 MHz) δ 173.0, 163.0 (dd, J_(C-F)=248, 2 Hz), 132.8 (dd,J_(C-F)=22, 3 Hz), 127.5 (dd, J_(C-F)=9, 6 Hz), 115.9 (d, J_(C-F)=22Hz), 81.3 (d, J_(C-F)=229 Hz), 28.3 (d, J_(C-F)=12 Hz), 19.3 (d,J_(C-F)=12 Hz).

trans-2-Fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (Rosenet al., J. Med. Chem. 2004, 47:5860-5871). To a solution of trans-ethyl2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylate (0.200 g, 0.884mmol) in methanol (1.8 mL) was added KOH (0.500 g, 8.84 mmol) dissolvedin methanol (4.4 ml) at 0° C. The reaction mixture was warm to roomtemperature and stirred for 16 h. The mixture was poured into water andextracted with CH₂Cl₂ (25 mL). The organic layer was discarded and theaqueous layer was acidified with 6 M HCl and extracted with CH₂Cl₂ (2×25mL). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to affordtrans-2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (0.175g, 0.884 mmol, quant.) as a white solid: ¹H NMR (CDCl₃, 500 MHz) δ7.45-7.41 (m, 2H), 7.05 (t, J=8.6 Hz, 2H), 2.52 (ddd, J=17.4, 10.0, 7.5Hz, 1H), 1.94-1.83 (m, 2H); ¹³C NMR (CDCl₃, 100 MHz) δ 174.3, 163.4 (dd,J_(C-F)=249, 3 Hz), 130.6 (dd, J_(C-F)=9, 4 Hz), 128.6 (dd, J_(C-F)=21,3 Hz), 115.5 (d, J_(C-F)=22 Hz), 83.1 (d, J_(C-F)=222 Hz), 27.5 (d,J_(C-F)=17 Hz), 17.5 (d, J_(C-F)=10 Hz).

cis-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)cyclopropyl)-methanone.To a solution ofcis-2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (0.0500 g,0.252 mmol) in distilled CH₂Cl₂ (2.5 mL) at 0° C. was added1-(5-chloro-2-methylphenyl)piperazine hydrochloride (0.0750 g, 0.303mmol) and triethylamine (0.11 mL, 0.757 mmol). The cooled solution wasthen treated with T3P (50 wt. % solution in EtOAc, 0.27 mL, 0.378 mmol)dropwise. The reaction mixture was stirred at 0° C. for 30 min andallowed to warm to room temperature and stirred for 16 h. The reactionwas diluted with CH₂Cl₂ (30 mL) and washed with 1 M HCl (20 mL),saturated NaHCO₃ (20 mL), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude brown oil residue was purified viaflash column chromatography on SiO₂ (2:3 EtOAc/hexanes) to affordcis-(4-(5-chloro-2-methylphenyl)-piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)cyclopropyl)methanone(79.1 mg, 0.200 mmol, 79%) as a white solid: Mp 110.2-110.8° C.(hexanes); IR (CDCl₃) 2918, 2819, 1646, 1593, 1516, 1430, 1223, 831,809, 730 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.26 (m, 2H), 7.10 (t, J=7.8Hz, 3H), 6.98 (dd, J=8.1, 1.9 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 4.04-4.01(m, 1H), 3.67-3.57 (m, 3H), 2.92-2.79 (m, 4H), 2.39 (dt, J=20.7, 7.6 Hz,1H), 2.25 (s, 3H), 2.19 (ddd, J=9.8, 7.9, 4.6 Hz, 1H), 1.63-1.58 (m,2H); ¹³C NMR (CDCl₃, 150 MHz) δ 164.7, 162.6 (d, J_(C-F)=248 Hz), 152.0,133.9 (d, J_(C-F)=22 Hz), 132.2 (d, J_(C-F)=24 Hz), 132.0, 131.1,125.6-125.5 (m), 123.8 (d, J_(C-F)=25 Hz), 119.9 (d, J_(C-F)=22 Hz),116.2-115.9 (m), 79.9 (d, J=222 Hz), 52.1, 51.7, 46.2, 43.0, 30.5 (d,J_(C-F)=14 Hz), 17.7 (d, J_(C-F)=12 Hz), 17.6; ¹⁹F NMR (CDCl₃, 470 MHz)δ −113.88 (s, 1 F), −188.55 (s, 1 F); HRMS (ESI) m/z calcd forC₂₁H₂₂ClF₂N₂O ([M+H]⁺) 391.1383, found 391.1386.

trans-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)-cyclopropyl)methanone.To a solution of trans-2-fluoro-2-(4-fluorophenyl)cyclopropane-1-carboxylic acid (0.0500 g,0.252 mmol) in distilled CH₂Cl₂ (2.5 mL) at 0° C. was added1-(5-chloro-2-methylphenyl)-piperazine hydrochloride (0.0750 g, 0.303mmol) and triethylamine (0.11 mL, 0.757 mmol). The cooled solution wasthen treated with T3P (50 wt. % solution in EtOAc, 0.27 mL, 0.378 mmol)dropwise. The reaction mixture was stirred at 0° C. for 30 min andallowed to warm to room temperature and stirred for 16 h. The reactionwas diluted with CH₂Cl₂ (30 mL) and washed with 1 M HCl (20 mL),saturated NaHCO₃ (20 mL), dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The crude brown oil residue was purified viaflash column chromatography on SiO₂ (2:3 EtOAc/hexanes) to affordtrans-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)cyclopropyl)methanone(76.0 mg, 0.195 mmol, 77%) as a colorless oil: IR (CDCl₃) 2922, 2855,1641, 1593, 1517, 1432, 1225, 1193, 812, 735. ¹H NMR (CDCl₃, 500 MHz) δ7.34-7.30 (m, 2H), 7.10-7.06 (m, 3H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.74(d, J=2.1 Hz, 1H), 3.78-3.75 (m, 1H), 3.66 (t, J=5.0 Hz, 2H), 3.40 (ddd,J=12.4, 8.6, 3.3 Hz, 1H), 2.85-2.81 (m, 1H), 2.77-2.73 (m, 1H), 2.68(ddd, J=18.8, 10.9, 7.9 Hz, 1H), 2.38 (ddd, J=11.5, 8.3, 3.0 Hz, 1H),2.30 (dt, 1H, J=11.4, 5.7 Hz), 2.22 (s, 3H), 2.11 (dt, J=12.3, 7.6 Hz,1H), 1.84 (ddd, J=20.6, 10.8, 7.4 Hz, 1h); ¹³C NMR (CDCl₃, 100 MHz) δ165.3, 162.8 (d, J_(C-F)=248 Hz,), 151.8, 132.1 (d, J_(C-F)=21 Hz),131.1, 130.6 (dd, J_(C-F)=21, 3 Hz), 127.6 (d, J_(C-F)=7 Hz), 127.5,123.9, 119.8, 115.5 (d, J_(C-F)=22 Hz), 81.5 (d, J_(C-F)=222 Hz), 51.9,51.6, 46.1, 42.5, 29.6 (d, J_(C-F)=13 Hz), 17.5, 16.5 (d, J_(C-F)=10Hz); ¹⁹F NMR (CDCl₃, 470 MHz) δ −113.19 (s, 1 F), −164.01 (s, 1 F); HRMS(ESI) m/z calcd for C₂₁H₂₂ClF₂N₂O ([M+H]⁺) 391.1383, found 391.1384.

Racemictrans-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-fluoro-2-(4-fluorophenyl)-cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (30%MeOH, 7 mL/min, 220 nM, P=100) to afford(−)-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)(-2-fluoro-2-(4-fluorophenyl)cyclopropyl)methanone(retention time 4.76 min) as a colorless oil (100% purity by ESLD):[α]²⁰ _(D)−141.9 (c 0.84, MeOH); ¹H NMR (CDCl₃, 500 MHz) δ 7.35-7.31 (m,2H), 7.10-7.06 (m, 3H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.75 (d, J=2.1 Hz,1H), 3.78-3.74 (m, 1H), 3.69-3.64 (m, 2H), 3.43-3.38 (m, 1H), 2.85-2.81(m, 1H), 2.77-2.73 (m, 1H), 2.68 (ddd, J=18.8, 10.9, 7.9 Hz, 1H),2.41-2.37 (m, 1H), 2.31 (td, J=11.0, 5.4 Hz, 1H), 2.22 (s, 3H), 2.11(dt, J=12.3, 7.6 Hz, 1H), 1.84 (ddd, J=20.5, 10.8, 7.4 Hz,1H); HRMS(ESI) m/z calcd for C₂₁H₂₂ClF₂N₂O ([M+H]⁺) 391.1383, found 391.1379. Theenantiomeric excess was >99% ee (SFC Chiralpak-IC (250×10 mm); 30% MeOH,220 nm, 7 mL/min; retention time: 4.77 min).

(+)-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)(-2-fluoro-2-(4-fluorophenyl)cyclopropyl)-methanone(retention time 5.60 min) was obtained as a colorless oil (100% purityby ESLD): [α]²⁰ _(D)+145.1 (c 0.86, MeOH); ¹H NMR (CDCl₃, 500 MHz) δ7.34-7.31 (m, 2H), 7.10-7.06 (m, 3H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.75(d, J=2.0 Hz, 1H), 3.79-3.74 (m, 1H), 3.69-3.65 (m, 2H), 3.43-3.38 (m,1H), 2.85-2.81 (m, 1H), 2.77-2.73 (m, 1H), 2.68 (ddd, J=18.9, 10.9, 8.0Hz, 1H), 2.39 (ddd, J=11.2, 8.8, 2.6 Hz, 1H), 2.31 (dt, J=11.3, 5.8 Hz,1H), 2.22 (s, 3H), 2.11 (dt, J=12.3, 7.6 Hz, 1H), 1.84 (ddd, J=20.5,10.8, 7.4 Hz, 1H); HRMS (ESI) m/z calcd for C₂₁H₂₂ClF₂N₂O ([M+H]⁺)391.1383, found 391.1374. The enantiomeric excess was >99% ee (SFCChiralpak-IC (250×10 mm); 30% MeOH, 220 nm, 7 mL/min; retention time:5.60 min).

Ethyl 2-diazo-3,3,3-trifluoropropanoate (Bartrum et al., Chem. Eur. J.2011, 17:9586-9589; Shi et al., J. Org. Chem. 1990, 55:3383-3386). To astirred solution of p-toluenesulfonyl hydrazide (11.5 g, 60.5 mmol) indistilled CH₂Cl₂ (65 mL) was added ethyl trifluoropyruvate (7.79 mL,57.6 mmol). The reaction was stirred at room temperature for 18 h.Phosphorus oxychloride (7.05 mL, 74.9 mmol) was added dropwise followedby pyridine (6.11 mL, 74.9 mmol) (Note: when pyridine was added dropwisethe reaction mixture warmed up to a self-sustaining gentle reflux). Thereaction mixture was stirred at room temperature for another 18 h. Themixture was washed with water and the organic layer was separated. Theaqueous layer was extracted with CH₂Cl₂ (3×100 mL). The combined organiclayers were washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give ethyl3,3,3-trifluoro-2-(2-tosylhydrazineylidene)propanoate as a yellow liquidwhich solidified to a white solid upon standing. The crude product wasused in the next step without further purification.

To a solution of ethyl3,3,3-trifluoro-2-(2-tosylhydrazineylidene)propanoate (18.3 g, 54.1mmol) in anhydrous CH₂Cl₂ (433 mL) was added triethylamine (15.2 mL,0.108 mol) dropwise. The reaction mixture was stirred at roomtemperature for 2 days. The solution was carefully concentrated in vacuoand the crude product was purified via distillation. The distillate waswashed with 1 M HCl (20 mL×2) to remove the excess triethylamine. Theorganic layers collected were dried over anhydrous MgSO₄, filtered andcarefully concentrated in vacuo to afford ethyl2-diazo-3,3,3-trifluoropropanoate (4.89 g, 26.9 mmol, 50% over 2 steps)as a yellow oil: Bp lit: 60-62° C. (100 mmHg)⁴; ¹H NMR (CDCl₃, 500 MHz)δ 4.32 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 125MHz) δ 161.0, 122.8 (q, J_(C-F)=269 Hz), 62.3, 14.4 (C═N signal notobserved).

cis- and trans-Ethyl2-(4-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxylate. To aflame-dried flask containing 4-fluorostyrene (3.3 mL, 27.5 mmol) andRh₂(OAc)₄ (0.121 g, 0.275 mmol, 5 mol %) in distilled CH₂Cl₂ (25 mL) wasadded ethyl 2-diazo-3,3,3-trifluoropropanoate (1.00 g, 5.49 mmol) indistilled CH₂Cl₂ (20 mL) via a syringe pump over 16 h at roomtemperature. After consumption of the diazo compound by TLC, the mixturewas passed through a pad of silica gel to remove the rhodium catalystand washed with CH₂Cl₂. The solvent was removed in vacuo. The crudeproduct was purified by column chromatography (1:2 CH₂Cl₂/hexanes) togive an inseparable mixture of cis- and trans-ethyl2-(4-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxylate(cis/trans ratio 1:1.6) as an yellow oil (Note: The mixture alsocontained side product from the dimerization of the diazo compound):cis- (597 mg, 2.16 mmol, 34% calcd yield); ¹H NMR (CDCl₃, 500 MHz) δ7.26 (m, 2H), 7.00 (t, J=8.7 Hz, 2H), 4.33-4.25 (m, 2H), 3.04 (t, J=8.9Hz, 1H), 1.95 (ddq, J=9.5, 5.4, 1.8 Hz, 1H), 1.88 (dd, J=8.2, 5.3 Hz,1H), 1.34 (t, J=7.1 Hz, 3H); ¹⁹F NMR (CDCl₃, 470 MHz) δ −61.1 (s, 3 F),−114.5 (s, 1 F).

trans- (955 mg, 3.46 mmol, 54% calcd yield); ¹H NMR (CDCl₃, 500 MHz) δ7.22 (dd, J=8.2, 5.4 Hz, 2H), 6.98 (t, J=8.7 Hz, 2H), 3.96-3.87 (m, 2H),2.90 (t, J=9.0 Hz, 1H), 2.14-2.11 (m, 1H), 1.78 (dd, J=9.7, 5.7 Hz, 1H),0.94 (t, J=7.1 Hz, 3H); ¹⁹F NMR (CDCl₃, 470 MHz) δ −66.8 (s, 3 F),−114.5 (s, 1 F).

cis- andtrans-2-(4-Fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxylicacid. To a solution of to KOH (1.02 g, 18.1 mmol) in methanol (9 ml) wasadded cis- and trans-ethyl2-(4-fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxylate (0.500g, 1.81 mmol) dissolved in methanol (3.8 mL). The reaction mixture washeated to 55° C. and stirred at this temperature for 24 h. The mixturewas cooled to room temperature and poured into water and extracted withCH₂Cl₂ (25 mL). The organic layer was discarded and the aqueous layeracidified with 6 M HCl and extracted with CH₂Cl₂ (2×25 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give a mixture of cis- andtrans-2-(4-Fluorophenyl)-1-(trifluoromethyl)cyclopropane-1-carboxylicacid as a pale yellow solid (cis/trans ratio 1:1.16) which was used inthe next step without purification: cis- (168 mg, 0.677 mmol, 37% calcdyield); ¹H NMR (CDCl₃, 500 MHz) δ 7.29-7.26 (m, 2H), 7.02 (t, J=8.6 Hz,2H), 3.16 (t, J=9.0 Hz, 1H), 2.04-1.97 (m, 2H); ¹⁹F NMR (CDCl₃, 471 MHz)δ −61.5 (s, 3 F), −114.0 (s, 1 F).

trans- (262 mg, 1.06 mmol, 58% calcd yield); ¹H NMR (CDCl₃, 500 MHz) δ7.18 (dd, J=8.4, 5.4 Hz, 2H), 6.97 (t, J=8.6 Hz, 2H), 2.99 (t, J=9.0 Hz,1H), 2.09 (t, J=6.5 Hz, 1H), 1.84 (dd, J=9.7, 5.8 Hz, 1H); ¹⁹F NMR(CDCl₃, 470 MHz) δ −66.9 (s, 3 F), −114.1 (s, 1 F).

cis- andtrans-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)(2-(4-fluorophenyl)-1-(trifluoromethyl)-cyclopropyl)methanone.To a suspension of cis- andtrans-2-(4-Fluorophenyl)-1-(trifluoromethyl)-cyclopropane-1-carboxylicacid (0.250 g, 1.01 mmol) in distilled CH₂Cl₂ (10 mL) cooled to 0° C.was added oxalyl chloride (0.18 mL, 2.01 mmol) followed by a catalyticamount of DMF and the reaction was gradually warmed to room temperatureand stirred for another 2 h. The reaction was concentrated in vacuo(water bath 25° C.) to afford the yellow crude acid chloride. The cruderesidue formed above was dissolved in distilled CH₂Cl₂ (10 mL) cooled to0° C. and added with 1-(5-chloro-2-methylphenyl)piperazine hydrochloride(0.349 g, 1.41 mmol) and Et₃N (0.50 mL, 3.60 mmol) and the reaction wasallowed to warm to room temperature and stirred for 20 h. LCMS and NMRanalysis showed presence of starting material carboxylic acid (possiblydue to hydrolysis of the acyl chloride). The reaction mixture was cooledto 0° C. and T3P (50 wt. % in EtOAc, 0.85 mL, 1.21 mmol) was added tocouple the remaining of the carboxylic acid to the piperazine. Themixture was stirred at room temperature for 3 days until no startingmaterial was seen in LCMS. The reaction was diluted with CH₂Cl₂ (30 mL)and washed with saturated NaHCO₃ (20 mL), dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The crude oil residue was dissolvedpurified via flash column chromatography on SiO₂ (1:2 Et₂O/hexanes) toafford the cis- andtrans-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)(2-(4-fluorophenyl)-1-(trifluoromethyl)cyclopropyl)methanonerespectively as yellow oil: cis- (107 mg, 0.244 mmol, 24%); IR (CDCl₃)2926, 1647, 1515, 1438, 1226, 1153, 1125, 842, 738 cm⁻¹; ¹H NMR (CDCl₃,500 MHz) δ 7.32 (dd, J=8.5, 5.4 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H),7.05-7.00 (m, 3H), 6.96 (d, J=2.1 Hz, 1H), 3.88 (br s, 4H), 2.94 (br s,4H), 2.79 (t, J=8.7 Hz, 1H), 2.30 (s, 3H), 1.98 (dd, J=7.9, 6.2 Hz, 1H),1.73-1.69 (m, 1H); ¹³C NMR (CDCl₃, 151 MHz) δ 164.6, 162.3 (d, J=246Hz), 151.8, 132.3, 132.1, 131.1, 130.7 (d, J_(C-F)=8 Hz), 129.3 (d,J_(C-F)=3 Hz), 124.7 (q, J_(C-F)=276 Hz), 124.0, 120.0, 115.5 (d,J_(C-F)=21 Hz), 51.8, 47.1, 43.4, 34.8 (q, J_(C-F)=32 Hz), 27.6, 17.6,14.8; ¹⁹F NMR (CDCl₃, 470 MHz) δ −60.7 (s, 3 F), −114.8 (s, 1 F); HRMS(ESI) m/z calcd for C₂₂H₂₂ClF₄N₂O ([M+H]⁺) 441.1351, found 441.1352.

trans- (151 mg, 0.342 mmol, 34%); IR (CDCl₃) 2925, 2860, 1643, 1516,1437, 1226, 1149, 1132, 845, 812, 733 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ7.12-7.04 (m, 5H), 6.95 (dd, J=8.1, 2.1 Hz, 1H), 6.65 (d, J=1.7 Hz, 1H),3.77 (s, 1H), 3.49-3.47 (m, 2H), 3.03 (s, 1H), 2.80 (dd, J=9.8, 7.5 Hz,1H), 2.74-2.71 (m, 1H), 2.53-2.42 (m, 2H), 2.16 (s, 3H), 1.87 (t, J=7.0Hz, 1H), 1.79 (dd, J=9.8, 6.6 Hz, 1H), 1.51 (s, 1H); ¹³C NMR (CDCl₃, 101MHz) δ 162.6 (d, J_(C-F)=248 Hz), 161.7, 151.7, 132.1, 132.0, 131.1,130.9 (d, J_(C-F)=3 Hz), 128.8 (d, J_(C-F)=8 Hz), 124.6 (q, J_(C-F)=272Hz), 123.9, 119.8, 116.0 (d, J_(C-F)=22 Hz), 51.3, 50.9, 46.8, 43.2,36.8 (q, J_(C-F)=33 Hz), 27.3, 17.4, 15.5; ¹⁹F NMR (CDCl₃, 470 MHz) δ−66.3 (s, 3 F), −114.0 (s, 1 F); HRMS (ESI) m/z calcd for C₂₂H₂₂ClF₄N₂O([M+H]⁺) 441.1351, found 441.1349.

Racemiccis-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1SR,2SR)-2-(4-fluorophenyl)-1-(trifluoromethyl)cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (10%MeOH, 6 mL/min, 220 nM, P=100) to afford(−)-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(-2-(4-fluorophenyl)-1-(trifluoromethyl)cyclopropyl)methanone(retention time 14.46 min) as a colorless oil which foamed up upondrying (100% purity by ESLD): [a]²⁰ _(D)−57.3 (c 0.44, MeOH); ¹H NMR(CDCl₃, 500 MHz) δ 7.32 (dd, J=8.5, 5.4 Hz, 2H), 7.13 (d, J=8.1 Hz, 1H),7.05-7.00 (m, 3H), 6.96 (d, J=2.1 Hz, 1H), 3.89-3.88 (m, 4H), 2.94 (s,4H), 2.79 (t, J=8.7 Hz, 1H), 2.30 (s, 3H), 1.98 (dd, J=7.9, 6.2 Hz, 1H),1.71 (ddq, J=9.5, 6.0, 1.8 Hz, 1H). HRMS (ESI) m/z calcd forC₂₂H₂₂ClF₄N₂O ([M+H]⁺) 441.1348, found 441.1351. The enantiomeric excesswas >99% ee (SFC Chiralpak-IC (250×10 mm); 10% MeOH, 220 nm, 6 mL/min;retention time: 14.55 min).

(+)-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(-2-(4-fluorophenyl)-1-(trifluoromethyl)-cyclopropyl)methanone(retention time 16.17 min) was obtained as a colorless oil which foamedup upon drying (100% purity by ESLD): [a]²⁰ _(D)+58.4 (c 0.42, MeOH); ¹HNMR (CDCl₃, 500 MHz) δ 7.32 (dd, J=8.5, 5.3 Hz, 2H), 7.13 (d, J=8.1 Hz,1H), 7.05-7.00 (m, 3H), 6.96 (d, J=2.1 Hz, 1H), 3.89-3.88 (m, 4H), 2.94(s, 4H), 2.79 (t, J=8.7 Hz, 1H), 2.30 (s, 3H), 1.98 (dd, J=7.9, 6.2 Hz,1H), 1.71 (ddq, J=9.6, 6.0, 1.9 Hz, 1H); HRMS (ESI) m/z calcd forC₂₂H₂₂ClF₄N₂O ([M+H]⁺) 441.1348, found 441.1351. The enantiomeric excesswas >99% ee (SFC Chiralpak-IC (250×10 mm); 10% MeOH, 220 nm, 6 mL/min;retention time: 16.31 min).

1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (Miura et al., Chem.Lett. 2008, 37:1006-1007; Kobayashi et al., J. Fluorine Chem. 2009,130:591-594). To a solution of 1,2-dibromo-3,3,3-trifluoropropane (6.35mL, 52.0 mmol) in THF/DME/H2O (1:1:1, 105 mL), 4-fluorophenylboronicacid (5.00 g, 34.7 mmol), PdCl₂(PPh₃)₂ (0.973 g, 1.39 mmol), AsPh₃ (1.64g, 5.20 mmol), and KOH (11.7 g, 0.208 mol) were added under an inertatmosphere. The reaction mixture was stirred in an ice bath for 10 min,and gradually warmed up to room temperature and then heated at 75° C.for 13 h. After completion of reaction, water (200 mL) was added, thenthe mixture was extracted with diethyl ether (2×200 mL). The combinedorganic layers were washed with brine (300 mL) and dried over anhydrousMgSO₄. The solvent was carefully removed in vacuo. The crude materialwas purified via vacuum distillation to give1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (5.25 g, 82%) as acolorless oil: Bp 53° C. @ 20 mmHg; ¹H NMR (CDCl₃, 500 MHz) δ 7.43 (dd,J=8.6, 5.5 Hz, 2H), 7.10-7.05 (m, 2H), 5.95 (d, J=1.2 Hz, 1H), 5.73 (q,J=1.6 Hz, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ 163.4 (d, J_(C-F)=249 Hz),138.3 (q, J_(C-F)=30 Hz), 129.9 (d, J_(C-F)=4 Hz), 129.5 (d, J_(C-F)=8Hz), 123.4 (q, J_(C-F)=274 Hz), 120.6 (q, J_(C-F)=6 Hz), 115.7 (d,J_(C-F)=22 Hz); ¹⁹F NMR (CDCl₃, 471 MHz) δ −65.1 (s, 3 F), −112.5 (s, 1F).

cis- andtrans-Ethyl-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropane-1-carboxylate.To a flame-dried round-bottom flask was added Rh₂(OAc)₄ (128 mg, 0.290mmol, 5 mol %) and 1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene(1.20 g, 5.81 mmol) in distilled CH₂Cl₂ (5 mL). A solution of ethyldiazoacetate (1.04 mL, 8.71 mmol) in CH₂Cl₂ (18 mL) was added viasyringe pump over 16 h at room temperature. After addition of the diazocompound, TLC analysis showed that there was still presence of thealkene. Another 2 mol % of the Rh₂(OAc)₄ catalyst was added and 0.5equiv of diazo compound dissolved in CH₂Cl₂ (10 mL) was added dropwiseover 9 h. The mixture was filtered through a silica gel plug and washedwith CH₂Cl₂. The solution was concentrated under reduced pressure andthe crude mixture was purified via flash column chromatography on SiO₂(1:2 CH₂Cl₂/hexanes) to afford cis- andtrans-ethyl-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropane-1-carboxylaterespectively as yellow oils: cis- (554 mg, 2.01 mmol, 35%); ¹H NMR(CDCl₃, 500 MHz) δ 7.47 (dd, J=8.6, 5.3 Hz, 2H), 7.08-7.02 (m, 2H),4.32-4.18 (m, 2H), 2.23 (t, J=8.1 Hz, 1H), 2.04 (dd, J=7.2, 5.9 Hz, 1H),1.46 (ddq, J=8.9, 5.7, 1.7 Hz, 1H), 1.31 (t, J=7.1 Hz, 3H); ¹³C NMR(CDCl₃, 125 MHz) δ 168.0, 163.0 (d, J_(C-F)=248 Hz), 132.8 (d, J_(C-F)=9Hz), 131.8 (d, J_(C-F)=3 Hz), 125.2 (q, J_(C-F)=276 Hz), 115.7 (d,J_(C-F)=22 Hz), 61.7, 35.0 (q, J_(C-F)=34 Hz), 27.5, 14.5 (q, J_(C-F)=2Hz), 14.2; ¹⁹F NMR (CDCl₃, 471 MHz) δ −65.6 (s, 3 F), −112.4 (s, 1 F).

trans- (662 mg, 2.40 mmol, 41%); ¹H NMR (CDCl₃, 500 MHz) δ 7.34 (dd,J=8.6, 5.3 Hz, 2H), 7.05-7.00 (m, 2H), 4.01-3.91 (m, 2H), 2.48 (dd,J=8.8, 6.3 Hz, 1H), 1.83 (tq, J=5.8, 1.8 Hz, 1H), 1.72 (dd, J=8.8, 5.5Hz, 1H), 1.07 (t, J=7.1 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ 168.7, 163.0(d, J_(C-F)=248 Hz), 133.0 (d, J_(C-F)=9 Hz), 127.4 (d, J_(C-F)=3 Hz),125.0 (q, J_(C-F)=274 Hz), 115.6 (d, J_(C-F)=22 Hz), 61.3, 35.2 (q,J_(C-F)=34 Hz), 23.8 (q, J_(C-F)=2 Hz), 14.7 (q, J_(C-F)=2 Hz), 14.1;¹⁹F NMR (CDCl₃, 471 MHz) δ −70.7 (s, 3 F), −112.4 (s, 1 F). A fractioncontaining a mixture of both diastereomers was also obtained (192 mg,0.694 mmol, 12%).

cis-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropane-1-carboxylicacid. To a solution of KOH (0.463 g, 8.25 mmol) in methanol (3.6 ml) wasaddedcis-ethyl-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropane-1-carboxylate(0.228 g, 0.825 mmol) dissolved in methanol (1.5 mL) at 0° C. Thereaction mixture was gradually warm to room temperature and stirred for12 h. The mixture was poured into water and extracted with CH₂Cl₂ (25mL). The organic layer was discarded and the aqueous layer acidifiedwith 6 M HCl and extracted with CH₂Cl₂ (2×25 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give thecis-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropane-1-carboxylicacid (0.202 g, 0.812 mmol, 98%) as a white solid: ¹H NMR (CDCl₃, 500MHz) δ 7.47 (dd, J=8.6, 5.2 Hz, 2H), 7.09-7.02 (m, 2H), 2.28 (t, J=8.0Hz, 1H), 2.09 (dd, J=7.3, 5.9 Hz, 1H), 1.57-1.53 (m, 1H); ¹⁹F NMR(CDCl₃, 471 MHz) δ −65.3 (s, 3 F), −112.1 (s, 1 F).

trans-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropane-1-carboxylicacid. To a solution of KOH (0.406 g, 7.24 mmol) in methanol (3.6 ml) wasaddedtrans-ethyl-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropane-1-carboxylate(0.200 g, 0.724 mmol) dissolved in methanol (1.5 mL) at 0° C. Thereaction mixture was gradually warm to room temperature and stirred for12 h. The mixture was poured into water and extracted with CH₂Cl₂ (25mL). The organic layer was discarded and the aqueous layer acidifiedwith 6 M HCl and extracted with CH₂Cl₂ (2×25 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to give thetrans-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropane-1-carboxylicacid (0.181 g, 0.731 mmol, 98%) as a white solid: ¹H NMR (CDCl₃, 500MHz) δ 7.32 (dd, J=8.3, 5.4 Hz, 2H), 7.02 (t, J=8.6 Hz, 2H), 2.49-2.45(m, 1H), 1.77 (dq, J=8.3, 2.9 Hz, 2H); ¹⁹F NMR (CDCl₃, 471 MHz) δ −70.9(s, 3 F), −112.1 (s, 1 F).

cis-(4-(5-Chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropyl)methanone.A solution ofcis-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropane-1-carboxylic acid(0.100 g, 0.403 mmol) and 1-(5-chloro-2-methylphenyl)piperazinehydrochloride (0.120 g, 0.484 mmol) in distilled CH₂Cl₂ (4 mL) wascooled to 0° C. and then added with triethylamine (0.168 mL, 1.21 mmol).The cooled solution was then treated with T3P (50 wt. % solution inEtOAc), 0.43 mL, 0.604 mmol) dropwise. The reaction mixture was stirredat 0° C. for 30 min and allowed to warm to room temperature and stirredfor 18 h. After completion of the reaction by TLC analysis, the reactionwas diluted with CH₂Cl₂ (30 mL) and washed with 1 M HCl (30 mL),saturated NaHCO₃ solution (20 mL), dried over anhydrous MgSO₄, filteredand concentrated in vacuo. The brown crude oil residue was purified viaautomated flash column chromatography on SiO₂ (100 hexanes-40%EtOAc/hexanes gradient) to affordcis-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropyl)methanone(108 mg, 0.245 mmol, 61%) as a colorless oil which foamed up upondrying: IR (CDCl₃) 2917, 2825, 1651, 1593, 1513, 1435, 1227, 1159, 1137,835, 727 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 7.47 (dd, J=8.7, 5.2 Hz, 2H),7.14-7.06 (m, 3H), 7.00 (dd, J=8.1, 2.1 Hz, 1H), 6.97 (d, J=2.1 Hz, 1H),3.99-3.87 (m, 3H), 3.81-3.76 (m, 1H), 3.01 (t, J=5.0 Hz, 2H), 2.94-2.86(m, 2H), 2.31 (s, 3H), 2.22-2.17 (m, 2H), 1.60-1.56 (m, 1H); ¹³C NMR(CDCl₃, 125 MHz) δ 164.9, 162.9 (d, J_(C-F)=249 Hz), 152.0, 132.3,132.0, 131.8 (d, J_(C-F)=8 Hz), 131.1, 125.6 (q, J_(C-F)=276 Hz), 123.9,119.9, 116.0 (d, J_(C-F)=22 Hz), 51.7, 51.6, 46.3, 42.9, 35.1 (q,J_(C-F)=34 Hz), 28.1, 17.60, 14.55; ¹⁹F NMR (CDCl₃, 471 MHz) δ −64.7 (s,3 F), −112.2 (s, 1 F); HRMS (ESI) m/z calcd for C₂₂H₂₂ClF₄N₂O ([M+H]⁺)441.1351, found 441.1350.

trans-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1RS,2RS)-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropyl)methanone.A solution oftrans-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropane-1-carboxylicacid (0.100 g, 0.403 mmol) and 1-(5-chloro-2-methylphenyl)piperazinehydrochloride (0.120 g, 0.484 mmol) in distilled CH₂Cl₂ (4 mL) wascooled to 0° C. and then added with triethylamine (0.168 mL, 1.21 mmol).The cooled solution was then treated with T3P (50 wt. % solution inEtOAc), 0.43 mL, 0.604 mmol) dropwise. The reaction mixture was stirredat 0° C. for 30 min and allowed to warm to room temperature and stirredfor 18 h. After completion of the reaction by TLC analysis, the reactionwas diluted with CH₂Cl₂ (30 mL) and washed with 1 M HCl (30 mL),saturated NaHCO₃ solution (20 mL), dried over anhydrous MgSO₄, filteredand concentrated in vacuo. The brown crude oil residue was purified viaautomated flash column chromatography on SiO₂ (100 hexanes-40%EtOAc/hexanes gradient) to affordtrans-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropyl)methanone(162 mg, 0.367 mmol, 91%) as a colorless oil which foamed up upondrying: IR (CDCl₃) 2894, 2820, 1652, 1593, 1514, 1436, 1296, 1226, 1160,1143, 830, 735; ¹H NMR (CDCl₃, 500 MHz) δ 7.31 (dd, J=8.6, 5.3 Hz, 2H),7.13 (d, J=8.1 Hz, 1H), 7.06-7.00 (m, 3H), 6.96 (d, J=2.0 Hz, 1H),3.99-3.86 (m, 2H), 3.70-3.56 (m, 2H), 3.07-2.99 (m, 2H), 2.86-2.75 (m,2H), 2.59 (dd, J=8.8, 6.2 Hz, 1H), 2.30 (s, 3H), 2.12-2.09 (m, 1H), 1.70(dd, J=8.8, 5.3 Hz, 1H); ¹³C NMR (CDCl₃, 101 MHz) δ 165.3, 162.9 (d,J_(C-F)=248 Hz), 151.8, 132.8 (d, J_(C-F)=8 Hz), 132.3, 132.1, 131.1,127.1 (d, J_(C-F)=3 Hz), 125.4 (q, J_(C-F)=274 Hz), 124.0, 119.8, 115.8(d, J_(C-F)=22 Hz), 52.1, 51.7, 46.2, 42.8, 34.9 (q, J_(C-F)=33 Hz),22.8, 17.6, 13.9. ¹⁹F NMR (CDCl₃, 471 MHz) δ −69.6 (s, 3 F), −112.4 (s,1 F); HRMS (ESI) m/z calcd for C₂₂H₂₂ClF₄N₂O ([M+H]⁺) 441.1351, found441.1351.

Racemictrans-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)((1SR,2RS)-2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropyl)methanonewas separated on a SFC Chiralpak-IC semiprep (250×10 mm) column (13%MeOH, 7 mL/min, 220 nM, P=100) to afford(−)-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(2-(4-fluorophenyl)-2-(trifluoromethyl)cyclopropyl)methanone(retention time 6.01 min) as a colorless oil which foamed up upon drying(100% purity by ESLD): [a]²⁰ _(D)−179.6 (c 0.69, MeOH); ¹H NMR(CDCl_(3, 400) MHz) δ 7.31 (dd, J=8.6, 5.3 Hz, 2H), 7.13 (d, J=7.6 Hz,1H), 7.07-7.00 (m, 3H), 6.96 (d, J=2.1 Hz, 1H), 3.99-3.85 (m, 2H),3.71-3.54 (m, 2H), 3.08-2.98 (m, 2H), 2.86-2.74 (m, 2H), 2.59 (dd,J=8.8, 6.1 Hz, 1H), 2.30 (s, 3H), 2.13-2.08 (m, 1H), 1.70 (dd, J=8.8,5.3 Hz, 1H); HRMS (ESI) m/z calcd for C₂₂H₂₂ClF₄N₂O ([M+H]⁺) 441.1344,found 441.1351. The enantiomeric excess was >99% ee (SFC Chiralpak-IC(250×10 mm); 10% MeOH, 220 nm, 7 mL/min; retention time: 6.01 min).

(+)-(4-(5-chloro-2-methylphenyl)piperazin-1-yl)(2-(4-fluorophenyl)-2-(trifluoromethyl)-cyclopropyl)methanone(retention time 7.16 min) was obtained as a colorless oil which foamedup upon drying (100% purity by ESLD): [a]²⁰ _(D)−177.9 (c 0.67, MeOH);NMR (CDCl₃, 400 MHz) δ 7.31 (dd, J=8.6, 5.3 Hz, 2H), 7.13 (d, J=8.1 Hz,1H), 7.07-7.00 (m, 3H), 6.96 (d, J=2.1 Hz, 1H), 3.99-3.85 (m, 2H),3.71-3.54 (m, 2H), 3.07-3.00 (m, 2H), 2.87-2.74 (m, 2H), 2.59 (dd,J=8.9, 6.1 Hz, 1H), 2.30 (s, 3H), 2.12-2.08 (m, 1H), 1.70 (dd, J=8.8,5.3 Hz, 1H); HRMS (ESI) m/z calcd for C₂₂H₂₂ClF₄N₂O ([M+H]⁺) 441.1340,found 441.1351. The enantiomeric excess was >99% ee (SFC Chiralpak-IC(250×10 mm); 13% MeOH, 220 nm, 7 mL/min; retention time: 7.12 min).

cis- andtrans-Ethyl-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate.To a flame-dried round-bottom flask was added rhodium acetate (64.2 mg,0.145 mmol) and 4-(trifluoromethyl)styrene in distilled CH₂Cl₂ (3 mL). Asolution of ethyl 2-diazo-3,3,3-trifluoropropanoate (0.793 g, 4.36 mmol)in distilled CH₂Cl₂ (10 mL) was added via a syringe pump over 18 h. Themixture was stirred for another 2 hour and then filtered through asilica gel plug and washed with CH₂Cl₂. The solution was concentratedunder reduced pressure and the crude residue was purified via flashcolumn chromatography on SiO₂ (1:2 CH₂Cl₂/hexanes) to afford cis- andtrans-ethyl-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylaterespectively as pale yellow oil: cis- (224 mg, 0.686 mmol, 24%); ¹H NMR(CDCl₃, 500 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H),4.35-4.27 (m, 2H), 3.11 (t, J=8.9 Hz, 1H), 1.99 (ddq, J=9.5, 5.5, 1.8Hz, 1H), 1.94 (dd, J=8.3, 5.4 Hz, 1H), 1.35 (t, J=7.1 Hz, 3H); ¹⁹F NMR(CDCl₃, 470 MHz) δ −61.1 (s, 3 F), −62.6 (s, 3 F).

trans- (435 mg, 1.33 mmol, 46%); ¹H NMR (CDCl₃, 500 MHz) δ 7.56 (d,J=8.1 Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 2.97 (t,J=8.9 Hz, 1H), 2.18 (ddq, J=8.0, 6.0, 2.0 Hz, 1H), 1.84 (dd, J=9.7, 5.8Hz, 1H), 0.91 (t, J=7.1 Hz, 3H); ¹⁹F NMR (CDCl₃, 470 MHz) δ −62.6 (s, 3F), −67.0 (s, 3 F). A fraction containing a mixture of bothdiastereomers was also obtained (157 mg, 0.481 mmol, 17%).

cis-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid. A solution ofcis-ethyl-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate(0.220 g, 0.674 mmol) in methanol (1.4 mL) was added to KOH (0.378 g,6.74 mmol) in methanol (3.4 ml). The reaction mixture was heated to 55°C. and stirred for 3 d. The mixture was cooled to room temperature andpoured into water and extracted with CH₂Cl₂ (15 mL). The organic layerwas discarded and the aqueous layer acidified with 6 M HCl and extractedwith CH₂Cl₂ (2×15 mL). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to givecis-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (0.190 g, 0.636 mmol, 94%) as a white solid: ¹H NMR (CDCl₃, 500MHz) δ 7.60 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 3.24 (t, J=9.1Hz, 1H), 2.10-2.04 (m, 2H); ¹³C NMR (CDCl₃, 125 MHz) δ 173.7, 137.1,130.4 (q, J_(C-F)=33 Hz), 130.0, 125.6 (q, J_(C-F)=4 Hz), 124.1 (q,J_(C-F)=272 Hz), 123.6 (q, J_(C-F)=275 Hz), 32.9 (q, J_(C-F)=34 Hz),32.6, 17.0; ¹⁹F NMR (CDCl₃, 470 MHz) δ −61.6 (s, 3 F), −62.7 (s, 3 F).

trans-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid. A solution oftrans-ethyl-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate(0.200 g, 0.613 mmol) in methanol (1.3 mL) was added to KOH (0.344 g,6.13 mmol) in methanol (3 mL). The reaction mixture was heated to 55° C.and stirred for 3 d. The mixture was cooled to room temperature andpoured into water and extracted with CH₂Cl₂ (15 mL). The organic layerwas discarded and the aqueous layer acidified with 6 M HCl and extractedwith CH₂Cl₂ (2×15 mL). The combined organic layers were dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to givetrans-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (187 mg, 0.627 mmol, quant.) as a white solid: ¹H NMR (CDCl₃, 500MHz) δ 7.54 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 3.04 (t, J=9.1Hz, 1H), 2.16-2.13 (m, 1H), 1.89 (dd, J=9.7, 5.9 Hz, 1H); ¹³C NMR(CDCl₃, 125 MHz) δ 170.7, 137.1 (d, J_(C-F)=1 Hz), 130.3 (q, J_(C-F)=33Hz), 129.6, 125.4 (q, J_(C-F)=4 Hz), 124.1 (q, J_(C-F)=272 Hz), 123.9(q, J_(C-F)=274 Hz), 34.3 (q, J_(C-F)=34 Hz), 30.1 (d, J_(C-F)=1 Hz),16.2; ¹⁹F NMR (CDCl₃, 470 MHz) δ −62.7 (s, 3 F), −67.1 (s, 3 F).

cis-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)methanone.A solution ofcis-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (50.0 mg, 0.168 mmol) and 1-(2,5-trifluoromethylphenyl)piperazinehydrochloride (73 mg, 0.218 mmol) in distilled CH₂Cl₂ (0.85 mL) wascooled to 0° C. and then added with triethylamine (0.12 mL, 0.838 mmol).The cooled solution was then treated with T3P (50 wt. % solution inEtOAc, 0.14 mL, 0.201 mmol) dropwise. The reaction mixture was stirredat 0° C. for 30 min and allowed to warm to room temperature and stirredfor 3 d. After completion of the reaction by TLC and LCMS analysis, thereaction mixture was diluted with CH₂Cl₂ (10 mL) and washed with 1 M HCl(10 mL), saturated NaHCO₃ (10 mL), dried over anhydrous MgSO₄, filteredand concentrated in vacuo. The crude residue was purified via automatedflash column chromatography on SiO₂ (1:3 EtOAc/hexanes) to affordcis-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)cyclopropylnnethanoneas a white solid (77.6 mg, 0.134 mmol, 80%): Mp 128.4-131.7° C.; IR(CDCl₃) 2925, 2833, 1648, 1425, 1326, 1313, 1122, 1085, 846, 736; NMR(CDCl₃, 500 MHz) δ 7.81 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.56(d, J=8.3 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 3.91-3.87 (m, 4H), 3.02 (t,J=4.6 Hz, 4H), 2.88 (t, J=8.6 Hz, 1H), 2.07 (t, J=7.1 Hz, 1H), 1.75 (t,J=7.8 Hz, 1H); ¹³C NMR (CDCl₃, 126 MHz) δ 164.2, 152.2, 137.8, 135.3 (q,J_(C-F)=33 Hz), 130.9 (q, J_(C-F)=29 Hz), 130.1 (t, J_(C-F)=33 Hz),129.5, 128.5 (q, J_(C-F)=5 Hz), 125.5 (q, J_(C-F)=4 Hz), 124.5 (q,J_(C-F)=281 Hz), 124.2 (q, J_(C-F)=272 Hz), 123.4 (q, J_(C-F)=274 Hz),123.2 (q, J_(C-F)=273 Hz), 122.6 (q, J_(C-F)=4 Hz), 121.2 (q, J_(C-F)=4Hz), 53.3, 53.2, 46.9, 43.1, 35.1 (q, J_(C-F)=33 Hz), 27.9, 14.8 (d,J_(C-F)=2 Hz); ¹⁹F NMR (CDCl₃, 470 MHz) δ −60.9 (d, 6 F), −62.6 (s, 3F), −63.2 (s, 3 F); HRMS (ESI) m/z calcd for C₂₄H₁₉F₁₂N₂O ([M+H]⁺)579.1300, found 579.1298.

trans-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(1-(trifluoromethyl)-2-(4-(trifluoromethyl)-phenyl)cyclopropyl)methanone.A solution oftrans-1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-cyclopropane-1-carboxylicacid (0.100 g, 0.335 mmol) and 1-(2,5-trifluoromethylphenyl)piperazinehydrochloride (0.146 g, 0.436 mmol) in distilled CH₂Cl₂ (1.7 mL) wascooled to 0° C. and then added with triethylamine (0.24 mL, 1.68 mmol).The cooled solution was then treated with T3P (50 wt. % solution inEtOAc, 0.28 mL, 0.402 mmol) dropwise. The reaction mixture was stirredat 0° C. for 30 min and allowed to warm to room temperature and stirredfor 4 d. After completion of the reaction by TLC and LCMS analysis, thereaction mixture was diluted with CH₂Cl₂ (15 mL) and washed with 1 M HCl(15 mL), saturated NaHCO₃ (15 mL), dried over anhydrous MgSO₄, filteredand concentrated in vacuo. The crude residue was purified via automatedflash column chromatography on SiO₂ (1:3 EtOAc/hexanes) to affordtrans-(4-(2,5-bis(trifluoromethyl)phenyl)piperazin-1-yl)(1-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-cyclopropylnnethanoneas colorless oil (51.5 mg, 0.0890 mmol, 27%): IR (CDCl₃) 2925, 2833,1643, 1510, 1424, 1310, 1115, 1070, 908, 851, 732 cm⁻¹; ¹H NMR (CDCl₃,500 MHz) δ 7.71 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.48 (d,J=8.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.14 (s, 1H), 4.06-4.01 (m, 1H),3.44-3.29 (m, 2H), 3.19-3.15 (m, 1H), 2.86 (dd, J=9.7, 7.5 Hz, 1H),2.82-2.80 (m, 1H), 2.56-2.43 (m, 2H), 1.98 (t, J=7.0 Hz, 1H), 1.86 (dd,J=9.7, 6.7 Hz, 1H), 1.20 (s, 1H); ¹³C NMR (CDCl₃, 125 MHz) δ 161.4,152.0, 139.6, 135.3 (q, J_(C-F)=33 Hz), 130.7 (q, J_(C-F)=29 Hz), 130.4(q, J_(C-F)=33 Hz), 128.4 (q, J_(C-F)=5 Hz), 127.7, 125.8 (q, J_(C-F)=4Hz), 124.5 (q, J_(C-F)=271 Hz), 123.9 (q, J_(C-F)=272 Hz), 123.2 (q,J_(C-F)=274 Hz), 123.1 (q, J_(C-F)=273 Hz), 122.4 (q, J_(C-F)=4 Hz),120.6 (q, J_(C-F)=3 Hz), 52.7, 52.4, 46.7, 43.1, 37.4 (q, J_(C-F)=33Hz), 27.5, 15.7; ¹⁹F NMR (CDCl₃, 470 MHz) δ −61.1 (s, 3 F), −62.8 (s, 3F), −63.5 (s, 3 F), −66.2 (s, 3 F); HRMS (ESI) m/z calcd forC₂₄H₁₉F₁₂N₂O ([M+H]⁺) 579.1300, found 579.1299.

(3,3-Difluoro-2-(4-(trifluoromethyl)phenyl)cycloprop-1-en-1-yl)(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone.Under an inert atmosphere,1-(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one(0.400 g, 0.908 mmol), TMSCF₂Br (0.28 mL, 1.82 mmol), nBu₄NBr (14.6 mg,0.0454 mmol), and toluene (3.6 mL) were added into an oven-driedpressure tube at room temperature. After being heated at 110° C. for 20h. The reaction mixture was cooled to room temperature and poured intosaturated NaHCO₃ solution (15 mL) and extracted with EtOAc (2×20 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. The crude product was subjectedto flash column chromatography on SiO₂ (1:9 EtOAc/hexanes). Thefractions collected contained ˜10% of impurities. The product wasresubjected to flash column chromatography on SiO₂ (1:2 CH₂Cl₂/hexanes)to afford(3,3-difluoro-2-(4-(trifluoromethyl)phenyl)cycloprop-1-en-1-yl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone(0.325 g, 0.663 mmol, 73%) as a pale yellow oil that foamed up upondrying under vacuum: IR (CDCl₃) 2925, 2825, 1776, 1643, 1442, 1303,1120, 1061, 1031, 909, 850, 730 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ 8.13 (d,J=8.0 Hz, 2H), 7.79 (d, J=8.1 Hz, 2H), 7.31 (q, J=8.7 Hz, 2H), 7.22 (s,1H), 3.94 (t, J=4.7 Hz, 2H), 3.88 (t, J=5.0 Hz, 2H), 3.04 (dt, J=25.5,5.0 Hz, 4H), 2.41 (s, 3H); ¹³C NMR (CDCl₃, 125 MHz) δ 155.1, 150.9,137.0, 135.5 (t, J=10 Hz), 134.4 (q, J=33 Hz), 132.6, 131.8, 129.4 (q,J=32 Hz), 126.3 (q, J=3.6 Hz), 126.0, 124.3 (q, J=272 Hz), 123.6 (q,J=273 Hz), 120.9 (q, J=3.9 Hz), 119.7 (t, J=13 Hz), 116.3 (q, J=3.6 Hz),98.8 (t, J=278 Hz), 52.2, 51.5, 46.9, 42.6, 18.1; ¹⁹F NMR (CDCl₃, 470MHz) δ −62.3 (s, 3 F), −63.2 (s, 3 F), −102.3 (s, 2 F); HRMS (ESI) m/zcalcd for C₂₃H₁₉ON₂F₈ ([M+H]⁺) 491.1364, found 491.1363.

cis-((1SR,3RS)-2,2-difluoro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone.A solution of(3,3-difluoro-2-(4-(trifluoromethyl)-phenyl)cycloprop-1-en-1-yl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanone(260 mg, 0.530 mmol) in EtOAc (4.6 mL) was added Pd/C (10% Pd on carbon,56.4 mg, 10.0 mol %). The reaction vessel was placed in the parrhydrogenator (7 bar) and stirred for 24 h at room temperature. Themixture was filtered through celite and concentrated in vacuo. The crudeoil was then passed through a plug of silica gel to remove baselineimpurities. The crude residue (270 mg) contained a mixture of thedesired cis-product and ring-opening side products which was inseparableby normal phase column chromatography.

The crude racemiccis-((1SR,3RS)-2,2-difluoro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)methanonewas purified and separated on a SFC Chiralpak-IC semiprep (250×10 mm)column (15% iPrOH, 6 mL/min, 220 nM, P=100) to afford the (−)-enantiomer(45.1 mg, 0.0916 mmol, 17%) and (+)-enantiomer (41.3 mg, 0.0839 mmol,16%) respectively as a white solid: Mp 123.5-127.8° C.; IR (CDCl₃) 2917,2820, 1648, 1416, 1323, 1308, 1115, 1070, 986, 856, 731 cm⁻¹.

(−)-2,2-difluoro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone(retention time 7.52 min) was obtained as a white solid (99.5% purity byESLD): [a]²⁰ _(D)−32.1 (c 1.03, iPrOH); ¹H NMR (CDCl₃, 500 MHz) δ 7.60(d, J=8.3 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.28-7.24 (m, 4H), 7.02 (s,1H), 3.80-3.77 (m, 1H), 3.66-3.53 (m, 3H), 3.13 (td, J=12.6, 2.0 Hz,1H), 2.90 (td, J=12.5, 2.4 Hz, 1H), 2.83 (dtd, J=11.5, 5.8, 3.4 Hz, 2H),2.61 (ddd, J=11.2, 8.0, 3.0 Hz, 1H), 2.39-2.33 (m, 1H), 2.31 (s, 3H);¹⁹F NMR (CDCl₃, 470 MHz) δ −62.4 (s, 3 F), −62.8 (s, 3 F), −118.9 (d,J_(F-F)=161 Hz, 1 F), −147.2 (d, J_(F-F)=161 Hz, 1 F); HRMS (ESI) m/zcalcd for C₂₃H₂₁ON₂F₈ ([M+H]⁺) 493.1521, found 493.1522. Theenantiomeric excess was >99% ee (SFC Chiralpak-IC (250×10 mm); 15%iPrOH, 220 nm, 6 mL/min; retention time: 7.54 min).

(+)-2,2-difluoro-3-(4-(trifluoromethyl)phenyl)cyclopropyl)(4-(2-methyl-5-(trifluoromethyl)-phenyl)piperazin-1-yl)methanone(retention time 9.64 min) was obtained as a white solid (99.5% purity byESLD): [a]²⁰ _(D)+33.5 (c 0.60, iPrOH); ¹H NMR (CDCl₃, 500 MHz) δ 7.60(d, J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.28-7.24 (m, 5H), 7.02 (s,1H), 3.81-3.76 (m, 1H), 3.66-3.52 (m, 3H), 3.13 (td, J=12.6, 2.2 Hz,1H), 2.90 (td, J=12.5, 2.6 Hz, 1H), 2.83 (dtd, J=11.5, 5.8, 3.3 Hz, 2H),2.61 (ddd, J=11.4, 7.9, 3.0 Hz, 1H), 2.39-2.33 (m, 1H), 2.31 (s, 3H);¹³C NMR (CDCl₃, 126 MHz) δ 160.94 (s, 1 C), 150.94 (s, 1 C), 136.92 (s,1 C), 134.96 (s, 1 C), 131.67 (s, 1 C), 130.13 (q, J=32.8 Hz, 1 C),129.53 (d, J=2.7 Hz, 1 C), 129.30 (q, J=34.0 Hz, 1 C), 125.39 (q, J=3.6Hz, 1 C), 124.22 (q, J=272.0 Hz, 1 C), 124.06 (q, J=272.1 Hz, 1 C),120.72 (q, J=3.7 Hz, 1 C), 116.01 (q, J=3.6 Hz, 1 C), 110.99 (t, J=289.7Hz, 1 C), 51.70 (s, 1 C), 51.49 (s, 1 C), 46.17 (s, 1 C), 42.12 (s, 1C), 31.35 (dd, J=12.9, 9.8 Hz, 1 C), 30.28 (dd, J=10.4, 8.9 Hz, 1 C),18.00 (s, 1 C). ¹⁹F NMR (CDCl₃, 470 MHz) δ −62.4 (s, 3 F), −62.8 (s, 3F), −118.9 (d, J_(F-F)=161 Hz, 1 F), −147.2 (d, J_(F-F)=161 Hz, 1 F).HRMS (ESI) m/z calcd for C₂₃H₂₁ON₂F₈ ([M+H]⁺) 493.1521, found 493.1522.The enantiomeric excess was >99% ee (SFC Chiralpak-IC (250×10 mm); 15%iPrOH, 220 nm, 6 mL/min; retention time: 9.66 min).

1-(3-Bromoprop-1-en-2-yl)-4-fluorobenzene. A solution of4-fluoro-a-methylstyrene (4.78 g, 35.1 mmol) in CDCl₃ (7 mL) was treatedwith NBS (8.50 g, 47.7 mmol, 1.36 eq). The reaction was heated to reflux(˜90° C.) for 6 h then it was cooled and filtered through Celite. Thefilter cake was then washed with hexane (50 mL) and the eluent wasconcentrated. The residue was purified by chromatography on SiO₂(hexane) to afford the allylic bromide (3.38 g, 15.7 mmol, 45%) as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.43 (m, 2H), 7.13-7.01(m, 2H), 5.50 (s, 1H), 5.48 (s, 1H), 4.36 (s, 2H); ¹⁹F NMR (376 MHz,CDCl₃) δ −113.7.

1-(2,2-Dibromo-1-(bromomethyl)cyclopropyl)-4-fluorobenzene. A solutionof allylic bromide (3.17 g, 14.7 mmol) and cetyltrimethyl ammoniumbromide (0.054 g, 0.15 mmol, 1 mol %) in CH₂Cl₂ (4 mL) was charged to a100 mL 3-neck flask affixed with an N₂ inlet, mechanical stirrer, andseptum. Bromoform (3.9 mL, 44 mmol, 3.0 eq) was added by syringe, andthe solution was cooled to 0° C. Sodium hydroxide (7.07 g, 0.177 mol)was added as a solution in water (15 mL, ˜50 g/100 mL) via syringe over5 min. The ice bath was removed and the flask stirred for 26 h at 300rpm over which period the color changed from clear to a dark, opaquebrown. The reaction mixture was then partitioned between water (50 mL)and CH₂Cl₂ (50 mL). The layers were separated, and the aqueous phase wasextracted with CH₂Cl₂ (50 mL). The combined extracts were washed withwater (25 mL), 1:1 water/brine (25 mL), and then were dried (Na₂SO₄) andconcentrated. The residue was purified by column chromatography on SiO₂(10% EtOAc in hexane). Upon concentration of the product-containingfractions, a solid mass formed. This material was then recrystallizedfrom ˜1:1 EtOAc/hexanes (˜15 mL), and the crystals were washed with coldhexanes (30 mL). After drying under vacuum, the tribromide (1.68 g, 4.35mmol, 30%) was obtained as a colorless crystalline solid: Mp 101-103°C.; ¹H NMR (300 MHz, CDCl₃) δ 7.38-7.30 (m, 2H), 7.08 (app t, 2H, J=3.3Hz), 3.91 (dd, 2H, J=7.8 Hz, 1.2 Hz), 3.82 (d, 1H, J=7.8 Hz), 2.21 (dd,1H, J=6.0 Hz, 0.9 Hz), 2.01 (d, 1H, J=6.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃)δ −113.2.

3-(4-Fluorophenyl)bicyclo[1.1.0]butane-1-carboxylic acid. A solution oftribromide (0.880 g, 2.57 mmol) in Et₂O (7 mL) and THF (3 mL, necessaryfor solubility) in a 50 mL round bottom flask was placed under N₂ andcooled to −78° C. MeLi (1.6 mL, 2.6 mmol, 1.0 eq, 1.6 M in ether) wasadded via syringe over 10 min. After 1.75 h at −78° C., t-BuLi (1.5 mL,2.6 mmol, 1.0 eq, 1.7 M in pentane) was added via syringe over 10 min.After an additional 1 h at −78° C., a ballon of dry CO₂ was bubbledthrough the solution via a needle for 10 min (external bubbler was used,and a continuous stream of CO₂ was passed through the flask). Thecooling bath was then removed, and the opaque grey reaction mixture waswarmed to 0° C. over 20 min. The reaction mixture was then quenched with1 M NaOH (10 mL), then the material was partitioned between ether and 1M NaOH (50 mL each). The light brown aqueous layer was acidified withcon HCl, forming an opaque solution with a light brown precipitate. Thissolution was then extracted with ether (2×40 mL). The organic layer wasdried (NaSO₄) and concentrated to afford the acid (0.228 g, 1.19 mmol,57%) as a buff solid: Mp 158-160° C.; IR (ATR) 1646, 1527, 1226, 841cm⁻¹; ¹H NMR (300 MHz, CD₃OD) δ 7.41-7.32 (m, 2H), 7.05 (app t, 2H,J=9.0 Hz), 2.88 (t, 2H, J=1.2 Hz), 1.60 (s, 2H); ¹³C NMR (100 MHz,CD₃OD) δ 172.2, 127.5 (³J_(CF)=8 Hz), 114.9 (²J_(CF)=21 Hz), 34.9, 31.8,22.4; ¹⁹F NMR (376 MHz, CD₃OD) δ −117.7; HRMS m/z calcd for C₁₁H₁₀FO₂[M+H] 193.0665, found 193.0660.

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(3-(4-fluorophenyl)bicyclo[1.1.0]butan-1-yl)methanone.A solution of bicyclobutane acid (0.018 g, 0.096 mmol, 1.1 eq) andpiperazine free base (0.023 g, 0.087 mmol) in CH₂Cl₂ (1 mL) was cooledto 0° C. and treated with Et₃N (0.02 mL, 0.2 mmol, 2 eq). Thetransparent beige solution was then treated with T3P (50% solution inEtOAc) (0.09 mL, 0.13 mmol, 1.5 eq) dropwise via syringe over ˜1 min.The reaction was stirred at 0° C. for 30 min, then the ice bath wasremoved and the reaction was warmed to rt for 19.5 h. The reactionmixture was then directly purified by chromatography on SiO₂ (15-25%EtOAc/hexanes) without workup to afford the amide (0.015 g, 0.038 mmol,39%) as a colorless oil: IR (ATR) 2923, 1620, 1596, 1434, 1307, 1221,1120, 1027, 906, 933, 725 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, 1H,J=8.4 Hz), 7.34-7.27 (m, 2H), 7.25-7.19 (m, 2H), 7.01 (app t, 2H,J=8.8), 4.1-3.5 (br m, 4H), 2.9-2.7 (br m, 4H), 2.75 (s, 2H), 1.63 (s,2H); ¹³C NMR (100 MHz, CDCl₃) δ 167.7, 161.9 (d, ¹ J_(CF)=243 Hz),152.9, 138.8, 135.1, 129.7 (d, ⁴J_(CF)=3 Hz), 128.6 (q, ³J_(CF)=5 Hz),128.0 (d, ³J_(CF)=8 Hz), 126.3 (q, ¹J_(CF)=272 Hz), 125.4 (q, ²J_(CF)=30Hz), 115.4 (d, ²J_(CF)=21 Hz), 36.9, 30.6, 21.0; ¹⁹F NMR (376 MHz,CDCl₃) δ −60.3, −115.9; MS (ESI)⁺ m/z 439 (100), 265 (3), 175 (5), 147(45); HRMS (ESI)⁺ m/z cald for C₂₂H₂₀ClF₄N₂O [M+H] 439.1195, found439.1193.

2-(4-(Trifluoromethyl)phenyl)prop-2-en-1-ol (Garzan et al., Chem. Eur.J. 2013, 19:9015-9021). Magnesium turnings (2.71 g, 0.111 mol) werecharged to a 500 mL 3-neck round bottomed flask fitted with a refluxcondenser, septum, and internal thermometer. After flushing with N₂, theturnings were suspended in ether (120 mL). 4-Trifluoromethylbromobenzene(15.8 mL, 0.111 mol) was added by syringe in ˜1 mL portions over ˜15min, which caused the formation of a dark brown Gringard solution andspontaneous heating of the reaction to reflux. After ˜1 h, the reactionhad cooled from reflux back to rt. To the freshly prepared Grignardreagent was added CuI (1.27 g, 6.67 mmol) and the black suspension wasstirred for 15 min. A solution of propargyl alcohol (2.60 mL, 44.6 mmol)in ether (50 mL) was added via cannula over 1.75 h, causing an exothermto 29° C. The reaction was then stirred at rt for 18 h, at which point aquenched aliquot showed consumption of propargyl alcohol by ¹H NMR. Thereaction was then cooled to 0° C. and quenched with sat aq NH₄Cl (100mL). The layers were separated and the aqueous layer was extracted withether (2×100 mL). The organic extracts were washed with water (100 mL)and brine (100 mL), then they were dried (MgSO₄), filtered, andconcentrated. The crude product was purified by chromatography on SiO₂(25% EtOAc/hexanes) to afford the alcohol (4.86 g, 24.0 mmol, 54%) as ared-tinted oil: ¹H NMR (400 MHz, CDCl₃) δ 7.58 (AB q, J=11.2 Hz,∂_(AB)=0.05 ppm), 5.55 (s, 1H), 5.46 (s, 1H), 4.56 (s, 2H).

(2,2-Dibromo-1-(4-(trifluoromethyl)phenyl)cyclopropyl)methanol. Asolution of alcohol (4.86 g, 24.0 mmol) in CH₂Cl₂ (40 mL) was treatedwith 3,4-dihydro-2H-pyran (3.1 mL, 34 mmol, 1.4 eq) followed by PPTS(0.604 g, 2.40 mmol, 0.10 eq). The resulting solution was stirred at rtfor 2.5 h. The reaction mixture was then concentrated on the rotovap.The residue was partitioned between ether and water (75 mL each). Thelayers were separated, and the organic layer was washed with sat aqNaHCO₃ (75 mL). The organic layer was then dried (Na₂SO₄) andconcentrated to afford the tetrahydropyran (7.11 g) as a red-tinted oil.The material contained residual solvents and was carried on withoutfurther purification.

A solution of protected alcohol (7.11 g, 24.8 mmol) and cetyltrimethylammonium bromide (0.091 g, 0.25 mmol, 1 mol %) in CH₂Cl₂ (12 mL) wasplaced in a 250 mL 3-neck flask was affixed with an N₂ inlet, mechanicalstirrer, and septum. Bromoform (6.5 mL, 75 mmol, 3.0 eq) was added, andthe solution was cooled to 0° C. Sodium hydroxide (11.9 g, 298 mmol,12.0 eq) was added as a solution in water (24 mL, ˜50 g/100 mL) viasyringe over 10 min. The ice bath was removed and the flask stirred atrt for 24 h at 300 rpm. ¹H NMR of an aliquot showed consumption of thealkene. The reaction mixture was then partitioned between water (50 mL)and CH₂Cl₂ (50 mL), the layers were separated, and the aqueous phase wasextracted with CH₂Cl₂ (50 mL). The combined extracts were washed withwater (25 mL), 1:1 water/brine (25 mL), then were dried (Na₂SO₄) andconcentrated.

This crude dark red oil was dissolved in MeOH (25 mL) and treated withtosic acid monohydrate (0.472 g, 2.48 mmol, 10 mol %). After stirring atrt for 3 h, the reaction mixture was concentrated. The residue waspartitioned between water and ether (75 mL each). The layers wereseparated and the organic layer was washed with water (75 mL), sat aqNaHCO₃ (75 mL), and brine (75 mL). The organic layer was then dried(Na₂SO₄) and concentrated. Purification by chromatography on SiO₂afforded the dibromocyclopropane (4.45 g, 11.9 mmol, 48% over 3 steps)as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.65 (app d, 2H, J=8.4Hz), 7.52 (app d, 2H, J=8.0 Hz), 4.01 (AB q, J=12.0 Hz, ∂_(AB)=0.04ppm), 2.11 (AB q, J=7.6 Hz, ∂_(AB)=0.03 ppm); ¹³C NMR (100 MHz, CDCl₃) δ142.4, 130.2, 125.4 (³J_(CF)=4 Hz), 70.1, 40.7, 31.9, 31.3, 21.1; ¹⁹FNMR (376 MHz, CDCl₃) δ −62.6.

1-(2,2-Dibromo-1-(bromomethyl)cyclopropyl)-4-(trifluoromethyl)benzene. Asolution of alcohol (4.45 g, 11.9 mmol) in CH₂Cl₂ (35 mL) was cooled to0° C. under N₂. PPh₃ (3.75 g, 13.1 mmol, 1.20 eq) was then charged,followed by CBr₄ (4.34 g, 13.1 mmol, 1.10 eq). The reaction was warmedto rt and stirred for 20 h, then it was concentrated. Purification bychromatography on SiO₂ (0-15% EtOAc in hexanes) afforded tribromide(4.31 g, 9.85 mmol, 83%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ7.66 (d, 2H, J=8.0 Hz), 7.49 (d, 2H, J=8.0 Hz), 3.93 (dd, 1H, J=10.8 Hz,1.2 Hz), 3.83 (d, 1H, J=10.8 Hz), 2.27 (dd, 1H, J=8.0 Hz, 1.2 Hz), 2.06(d, 1H, J=8.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 142.0, 130.6, 130.3, 125.4(q, ³J_(CF)=4 Hz), 41.7, 39.8, 34.8, 34.7, 33.4, 31.6, 14.1; ¹⁹F NMR(376 MHz, CDCl₃) δ −62.6.

3-(4-(Trifluoromethyl)phenyl)bicyclo[1.1.0]butane-1-carboxylic acid. Asolution of tribromide (1.50 g, 3.43 mmol) in Et₂O (15 mL) in a 50 mLround bottom flask was placed under N₂ and cooled to −78° C. MeLi (2.1mL, 3.4 mmol, 1.6 M in Et₂O) was added via syringe over 5 min. After 1 hat −78° C., t-BuLi (2.0 mL, 3.4 mmol, 1.7 M in pentane, 1.0 eq) wasadded via syringe over 5 min. After an additional 1 h at −78° C., aballoon of dry CO₂ was bubbled through the solution via a needle for 10min (external bubbler was used and a continuous stream of CO₂ was passedthrough the flask). The cooling bath was then removed, and the opaquegrey reaction mixture was warmed to 0° C. over 20 min while maintainingCO₂ bubbling. The reaction mixture was then quenched with 1 M NaOH (10mL), then it was partitioned between ether and 1 M NaOH (50 mL each).The light yellow aqueous layer was acidified with concentrated HCl,forming a colorless precipitate. This suspension was then extracted withether (2×40 mL). The organic layers were dried (Na₂SO₄) and concentratedto afford the acid (0.416 g, 1.72 mmol, 50%) as a colorless solid: Mp146-148° C.; IR (ATR) 2980, 1648, 1616, 1463, 1318, 1167, 1116, 1061,907, 842, 689 cm⁻¹; ¹H NMR (400 MHz, CD₃OD) δ 7.61 (d, 2H, J=8.4 Hz),7.52 (d, 2H, J=8.4 Hz), 4.88 (s, 1H), 2.99 (t, 2H, J=1.2 Hz), 1.68 (s,2H); ¹³C NMR (100 MHz, CD₃OD) δ 171.5, 140.0, 128.4 (q, ²J_(CF)=32 Hz),126.2, 124.9 (q, ³J_(CF)=4 Hz), 124.4 (q, ¹J_(CF)=269 Hz), 35.0, 31.0,24.2; ¹⁹F NMR (376 MHz, CDCl₃) δ −64.0; MS (ESI)⁺ m/z 243 (80), 233(50), 231 (50), 197 (60), 177 (40), 155 (100); HRMS (ESI)⁺ m/z cald forC₁₂H₁₀F₃O₂ [M+H] 243.0633, found 243.0626.

(4-(5-Chloro-2-(trifluoromethyl)phenyl)piperazin-1-yl)(3-(4-(trifluoromethyl)phenyl)-bicyclo[1.1.0]butan-1-yl)methanone.A solution of bicyclobutane acid (0.046 g, 0.19 mmol, 1.0 eq) andpiperazine HCl salt (0.057 g, 0.19 mmol) in CH₂Cl₂ (4 mL) cooled to 0°C. was treated Et₃N (0.08 mL, 0.6 mmol, 3 eq). The transparent beigesolution was then treated with T3P (50% solution in EtOAc) (0.20 mL,0.28 mmol, 1.5 eq) dropwise via syringe over 1 min. The reaction wasstirred at 0° C. for 30 min, then the ice bath was removed and thereaction was warmed to rt for 22 h. The reaction mixture was thenpartitioned between water and CH₂Cl₂ (30 mL each). The layers wereseparated, and the aqueous layer was extracted with additional CH₂Cl₂(30 mL). The combined extracts were washed with water (30 mL) and sat aqNaHCO₃ (30 mL), then were dried (Na₂SO₄) and concentrated. Purificationby chromatography on SiO₂ (15-25% EtOAc/hexanes) afforded the amide(0.051 g, 0.10 mmol, 55%) as a colorless solid: Mp 137-139° C.; IR (ATR)2902, 1604, 1466, 1438, 1312, 1100, 1027, 924, 838, 825 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 7.56 (app d, 3H, J=8.4 Hz), 7.43 (app d, 2H, J=8.4Hz), 7.23 (app q, 2H, J=8.4 Hz), 4.1-3.5 (br, 4H), 3.0-2.7 (br, 4H),2.83 (s, 2H), 1.69 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 167.1, 152.8,138.8, 138.6, 128.5 (q, ²J_(CF)=32), 128.5 (q, ³J_(CF)=4), 126.6, 125.7(q, ²J_(CF)=29), 125.5, 125.3 (q, ³J_(CF)=3), 124.6, 124.3 (q,¹J_(CF)=270), 123.6 (q, ¹J_(CF)=272), 37.0, 30.0, 29.7, 22.7; ¹⁹F NMR(376 MHz, CDCl₃) δ −60.3, −62.4; MS (ESI)⁺ m/z 489, 256 (5); HRMS (ESI)⁺m/z calcd for C₂₃H₂₀F₆ClN₂O [M+H] 489.1168, found 489.1158.

(4-(2-Methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(3-(4-(trifluoromethyl)phenyl)-bicyclo[1.1.0]butan-1-yl)methanone.Before this reaction was performed, the piperazine was free-based byshaking a solution of 66 mg (0.24 mmol, 1.1 eq) of HCl salt in CH₂Cl₂(30 mL) with 1 M NaOH (2×30 mL). The organic layer was then dried,concentrated, and the free base was used in the following reaction.

A solution of bicyclobutane acid (0.052 g, 0.21 mmol) and piperazinefree base in CH₂Cl₂ (2 mL) cooled to 0° C. and treated with Et₃N (0.06mL, 0.43 mmol, 2.0 eq). The transparent beige solution was treated withT3P (0.23 mL, 0.32 mmol, 1.5 eq, 50% solution in EtOAc) dropwise viasyringe. The reaction was stirred at 0° C. for 30 min, then the ice bathwas removed and the reaction was warmed to rt for 17 h. The reactionmixture was partitioned between water and CH₂Cl₂ (50 mL each). Thelayers were separated, and the aqueous layer was extracted withadditional CH₂Cl₂ (30 mL). The combined extracts were washed with water(50 mL) and sat aq NaHCO₃ (40 mL), then were dried (Na₂SO₄) andconcentrated. Purification by chromatography on SiO₂ (15-25%EtOAc/hexanes) afforded the amide (0.072 g, 0.154 mmol, 72%) as acolorless oil: IR (ATR) 2821, 1618, 1435, 1418, 1323, 1162, 1114, 1030,840, 732 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, 2H, J=8.0 Hz), 7.43(d, 2H, J=8.4 Hz), 7.28 (app q, 2H, J=8.0 Hz), 7.18 (s, 1H), 4.1-3.5(br, 4H), 3.0-2.7 (br, 4H), 2.84 (s, 2H), 2.36 (s, 3H), 1.70 (s, 2H);¹³C NMR (100 MHz, CDCl₃) δ 167.1, 151.2, 138.6, 136.8, 131.6, 129.1 (q,²J_(CF)=32), 128.5 (q, ²J_(CF)=32), 126.6, 125.3 (q, ³J_(CF)=4), 124.3(q, ^(1, J) _(CF)=270), 124.2 (q, ¹J_(CF)=271), 120.4 (q, ³J_(CF)=3),116.0 (q, ³J_(CF)=4), 37.0, 30.0, 22.8, 18.0; ¹⁹F NMR (376 MHz, CDCl₃) δ−62.2, −62.4; MS (ESI)⁺ m/z 469 (100), 197 (5); HRMS (ESI)⁺ m/z cald forC₂₄H₂₃F₆N₂O [M+H] 469.1709, found 469.1705.

(4-(2-methyl-5-(trifluoromethyl)phenyl)piperazin-1-yl)(3-(4-(trifluoromethyl)phenyl)cyclobutyl)-methanone.A solution of amide (0.072 g, 0.153 mmol) in MeOH (3 mL) was placedunder N₂ and treated with Pd/C (3 mg, 20 mol %). A hydrogen atmosphereof 6.43 bar was then established on the Parr hydrogenator. The reactionwas stirred at rt for 18 h, at which point the hydrogen was vented andthe solution was purified by chromatography on SiO₂ (25-40%EtOAc/hexanes) to afford the syn-cyclobutane (0.037 g, 0.079 mmol, 51%)as a colorless oil: IR (ATR) 2939, 1641, 1618, 1417, 1324, 1308, 1161,1112, 1067, 834, 732 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, 2H, J=8.4Hz), 7.36 (d, 2H, J=8.4 Hz), 7.32-7.24 (m, 2H, J=8.0 Hz), 7.19 (s, 1H),3.79 (t, 2H, J=4.8 Hz), 3.60 (t, 2H, J=5.2 Hz), 3.57-3.48 (m, 1H),3.37-3.26 (m, 1H), 2.95-2.86 (m, 4H), 2.68-2.59 (m, 2H), 2.53 (ddd, 2H,J=19.2 Hz, 9.6 Hz, 2.4 Hz), 2.84 (s, 2H), 2.37 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 172.4, 151.2, 148.6, 136.8, 131.6, 129.1 (q, ²J_(CF)=32),128.5 (q, ²J_(CF)=32), 127.4, 126.9, 126.7, 125.3 (q, ³J_(CF)=4), 124.3(q, ¹J_(CF)=270), 124.2 (q, ¹ J_(CF)=270), 120.4 (q, ³J_(CF)=4), 116.0(q, ³J_(CF)=5), 51.9, 51.7, 45.5, 42.2, 35.5, 33.1, 32.6, 17.6; ¹⁹F NMR(376 MHz, CDCl₃) δ −62.3; MS (ESI)⁺ m/z 471 (100), 355 (1), 246 (3), 179(3); HRMS (ESI)⁺ m/z cald for C₂₄H₂₅F₆N₂O [M+H] 471.1871, found471.1865.

Example 6 Androgen Receptor and Estrogen Receptor Alpha CompetitorAssays

The disclosed compounds are assayed for androgen receptor activity usingthe PolarScreen™ Androgen Receptor Competitor Assay Kit, Green(ThermoFisher Scientific, catalog #A15880). The kit uses rat AR-ligandbinding domain tagged with gluthathione-S-transferase (GST) andhistidine [AR-LBD(Hist-GST)] to determine the IC₅₀ of competitiveandrogen receptor compounds. AR-LBD(His-GST) is added tofluorescently-tagged androgen ligand (FluormoneAL Green) in the presenceof competitor test compounds. Effective competitors prevent theformation of a AL Green/AR-LBD(His-GST) complex, resulting in a decreaseof polarization due to ligand displacement by the competitor. The shiftin polarization values is used to determine the IC₅₀ of test compounds.

The disclosed compounds are assayed for estrogen receptor (ER) alphaactivity using the PolarScreen™ ER Alpha Compeitor Asssay Kit, Green(ThermoFisher Scientific, catalog #A15883). The kit uses full length,native (untagged), human estrogen receptor alpha to determine the IC₅₀of competitive estrogen receptor compounds. Full length ER alpha isadded to a fluorescent estrogen ligand (Fluormone ES2 Green) to form anER-Fluormone ES2 complex. An effective ER alpha competitor will displacethe Fluormone ES2 ligand from the ER alpha and will result in a decreasein polarization. The shift in fluorescence polarization is used todetermine the relative affinity of test compounds for ER alpha.

In view of the many possible embodiments to which the principles of thedisclosed compounds, compositions and methods may be applied, it shouldbe recognized that the illustrated embodiments are only preferredexamples and should not be taken as limiting the scope of the invention.

What is claimed is:
 1. A compound, or a stereoisomer, pharmaceuticallyacceptable salt, or ester thereof, selected from: (i) a compoundaccording to formula III

where the bond represented by “

” is a single or double bond, R²⁰ is (a) phenyl substituted with C₂-C₃perfluoroalkyl, halo, or pentafluorosulfanyl, (b) thiophenyl substitutedwith C₁-C₃ alkyl, or (c) cycloalkyl substituted with C₁-C₃perfluoroalkyl, R²³ is (a) phenyl mono- or di-substituted withsubstituents selected from halo, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl,pentafluorosulfanyl, cyano, —C(O)Oalkyl, or —C(O)N(H)alkyl, (b)pyrimidinyl, (c) cycloalkyl, or (d) heterocycloalkyl, R²⁴ and R²⁵ areabsent if the bond represented by “

” is a double bond, or R²⁴ and R²⁵ independently are hydrogen,deuterium, C₁-C₃ perhaloalkyl, halo, or cyano, or R²⁴ and R²⁵ togetherform —CH₂—, and R²⁶ and R²⁷ independently are hydrogen, deuterium, orhalo, wherein if R²⁴-R²⁷ are hydrogen, then R²⁰ is nothalogen-substituted phenyl; or (ii) a compound in Table A, where each Rindependently is C₁-C₃ perfluoroalkyl, halo, pentafluorosulfanyl,—C(O)Oalkyl, or C(O)N(H)alkyl, R²⁸ is O, N(CH₃), or CH₂, R²⁹ is N, O, orS, and R³⁰ is CH or N TABLE A


2. The compound of claim 1, wherein R²⁰ is: phenyl substituted with —SF₅or —F; or thiophenyl substituted with —CH₃; or cyclohexyl substitutedwith —CF₃.
 3. The compound of claim 2, wherein R²⁰ is phenyl orcyclohexyl and is substituted at the C4 position.
 4. The compound ofclaim 1, wherein R²³ is: phenyl substituted with —CF₃; or phenyldisubstituted with two halo substituents, halo and —CF₃, halo and —CH₃,or halo and cyano; or pyrimidinyl; or cyclohexyl; or heterocyclohexyl.5. The compound of claim 4, wherein R²³ is disubstituted phenyl and thetwo substituents are para to one another.
 6. The compound of claim 1,wherein the compound is:


7. The compound of claim 1, wherein the compound is:


8. A pharmaceutical composition comprising at least one pharmaceuticallyacceptable additive, and a compound of claim
 1. 9. A compound, or astereoisomer, pharmaceutically acceptable salt, or ester thereof,according to any one of formulas IV-XVII:

wherein R²⁰ is phenyl substituted with C₁-C₃ perfluoroalkyl, halo, orpentafluorosulfanyl; R²⁴-R²⁷ independently are hydrogen, deuterium, orhalo; R²⁸ is O, N(CH₃), or CH₂; R²⁹ is N, O, or S; R³⁰ is CH or N; eachR³¹ independently is C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, halo,pentafluorosulfanyl, —C(O)Oalkyl, or C(O)N(H)alkyl; and q is 1, 2, or 3.10. The compound of claim 9, wherein R²⁰ is phenyl substituted with—CF₃, —SF₅, or —F.
 11. The compound of claim 9, wherein R²⁰ issubstituted at the C3 or C4 position.
 12. The compound of claim 9,wherein each R³¹ independently is C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, orhalo.
 13. The compound of claim 9, wherein each R³¹ independently ismethyl, trifluoromethyl, or chloro.
 14. The compound of claim 9, whereinq is 2, and the R³¹ substituents are para to one another.
 15. Thecompound of claim 9, wherein the compound is:


15. A pharmaceutical composition comprising at least onepharmaceutically acceptable additive, and a compound of claim
 9. 16. Acompound, wherein the compound is:


17. A pharmaceutical composition comprising at least onepharmaceutically acceptable additive, and a compound of claim
 16. 18. Amethod for treating prostate cancer in a subject, comprisingadministering to the subject a therapeutically effective amount of acompound of claim
 1. 19. The method of claim 18, wherein: the compoundis orally administered; or the method is used in combination withandrogen deprivation therapy; or the compound is co-administered withabiratrone or enzalutamide.
 20. A method for treating prostate cancer ina subject, comprising administering to the subject a therapeuticallyeffective amount of a compound of claim
 9. 21. The method of claim 20,wherein: the compound is orally administered; or the method is used incombination with androgen deprivation therapy; or the compound isco-administered with abiratrone or enzalutamide.
 22. A method fortreating prostate cancer in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of claim 16.23. The method of claim 22, wherein: the compound is orallyadministered; or the method is used in combination with androgendeprivation therapy; or the compound is co-administered with abiratroneor enzalutamide.